19_04

SECTION 19.4

Cisplatin and Its Analogues

INTRODUCTION

The platinum drugs represent a unique and important class of antitumor compounds. Alone or in combination with other chemotherapeutic drugs,

cis-diamminedichloroplatinum (II) (cisplatin) and its analogues have made a significant impact on the treatment of a variety of solid tumors. The realization that

platinum complexes exhibit antitumor activity arose somewhat serendipitously in a series of experiments carried out by Rosenberg and colleagues beginning in 1961. 1

These studies involved determining the effect of electromagnetic radiation on the growth of bacteria in a chamber equipped with a set of platinum electrodes.

Exposure of the bacteria to an electric field resulted in a profound change in their morphology and, in particular, the appearance of long filaments that were several

hundred times longer than that of their untreated counterparts. This effect was not due to the electric field directly, but to the electrolysis products produced from the

platinum electrodes. An analysis of these products revealed that the predominant species was ammonium chloroplatinate [NH 4]2[PtCl6]. This compound was inactive at

reproducing the filamentous growth originally observed; however, Rosenberg and colleagues 1 soon discovered that the conversion of this complex to a neutral

species by UV light resulted in an active species. Attempts to synthesize the active neutral platinum complex failed. They realized, however, that the neutral

compound could exist in two isomeric forms, cis or trans, and that the latter species is the one they had synthesized. Subsequently, the cis isomer was synthesized

and shown to be the active compound.

The observation that cis-diamminedichloroplatinum (II) and cis-diamminetetrachloroplatinum (IV) inhibited bacterial growth led to the testing of four neutral platinum

compounds for antineoplastic activity in mice bearing the Sarcoma-180 solid tumor and L1210 leukemia cells. 2 All four compounds showed significant antitumor

activity, with cis-diamminedichloroplatinum (II) exhibiting the most efficacy. Further studies in other tumor models confirmed these results and indicated that cisplatin

exhibited a broad spectrum of activity. Although early clinical trials demonstrated significant activity against several tumor types, particularly testicular tumors, the

severe renal and gastrointestinal toxicity caused by the drug nearly led to its abandonment. Cvitkovic et al. 3,4 showed that these effects could be ameliorated, in part,

by aggressive prehydration, which rekindled interest in its clinical use. Currently, cisplatin is curative in testicular cancer and significantly prolongs survival in

combination regimens for ovarian cancer. The drug also has therapeutic benefit in head and neck, bladder, and lung cancer. 5

The unique activity and toxicity profile observed with cisplatin has fueled the development of platinum analogues that are less toxic and more effective against a

variety of tumor types, including those that have developed resistance to cisplatin. Two other platinum drugs are widely used: cis-diamminecyclobutanedicarboxylato

platinum (II) (carboplatin) and 1,2-diaminocyclohexaneoxalato platinum (II) (oxaliplatin). Several new analogues with unique activities are currently in various stages

of clinical development. Continued progress in the development of superior analogues requires a thorough understanding of the chemical, biological,

pharmacokinetic, and pharmacodynamic properties of this important class of drugs. A review of these properties is the focus of this chapter.

PLATINUM CHEMISTRY

Platinum exists primarily in either a 2+ or 4+ oxidation state. These oxidation states dictate the stereochemistry of the carrier ligands and leaving groups surrounding

the platinum atom. Platinum (II) compounds exhibit a square planar geometry, whereas platinum (IV) compounds exhibit an octahedral geometry. Interconversion of

the two oxidation states may readily occur. However, the kinetics of this reaction depend on the nature of the bound ligands. The nature of the ligands also determines

the stability of the complex and the rate of substitution. For platinum (II) compounds, the rate of substitution of a ligand is strongly influenced by the type of ligand

located opposite to it. Therefore, ligands that are bound more strongly stabilize the moieties that are situated trans to it. For cis-diamminedichloroplatinum (II), the two

chloride ligands are prone to substitution, whereas substitution of the amino groups is thermodynamically unfavorable. 6 The stereochemistry of platinum complexes is

critical to their antitumor activity, as evidenced by the significantly reduced efficacy observed with trans-diamminedichloroplatinum (II).

In aqueous solution, the chloride leaving groups of cisplatin are subject to mono- and diaqua substitution, particularly at chloride concentrations below 100 mmol,

which exist intracellularly. The equilibria may be described by the following two equations:

where equilibria constants for each reaction may be written

These descriptions illustrate the key role of ambient chloride concentrations in determining aquation rates. In weakly acidic solutions, the monochloromonoaqua and

diaqua complexes become deprotonated to form the neutral dihydroxo species. The monohydroxo and dihydroxo complexes are the predominant species present in

low chloride-containing environments, such as the nucleus. A detailed analysis of the equations and rate constants that govern these reactions has been published. 7

Based on studies of the reaction of cisplatin metabolites with inosine, the predominant cisplatin species that react with DNA are likely to be the chloroaqua and

hydroxoaqua species.7

EVOLUTION OF NOVEL PLATINUM COMPLEXES

Cisplatin therapy has two major limitations: an undesirable toxicity profile and the development of resistance by tumor cells. Therefore, substantial effort has gone into

developing analogues that are less toxic, with a different spectrum of antitumor activity. Progress in understanding the chemistry and pharmacokinetics of cisplatin

has guided the development of new analogues. In general, modification of the chloride leaving groups of cisplatin results in compounds with different

pharmacokinetics, whereas modification of the carrier ligands alters the activity of the resulting complex. This section summarizes the features of the more important

platinum analogues that have been developed, which are shown in Figure 19.4-1.

CARBOPLATIN

The search for a less toxic platinum drug, pursued at the Institute for Cancer Research in the United Kingdom, led to the development of carboplatin. 8,9 It was

hypothesized that modification of cisplatin to contain a more stable leaving group could alter toxicity without necessarily influencing the cytotoxicity profile. Using a

murine screen for nephrotoxicity, it was discovered that substituting a cyclobutanedicarboxylate moiety for the two chloride ligands of cisplatin resulted in a complex

with reduced renal toxicity. Instead, myelosuppression was dose-limiting, a toxicity that is not associated with cisplatin therapy. At effective doses, carboplatin

produces less nausea, vomiting, nephrotoxicity, and neurotoxicity than cisplatin and has demonstrated essentially equivalent survival rates in ovarian cancer patients.

Similar findings have been observed in other solid tumors. Therefore, based on its superior therapeutic index, greater ease of administration, and more predictable

individualized dosing, carboplatin has replaced cisplatin in many chemotherapeutic regimens.

1,2-DIAMINOCYCLOHEXANE DERIVATIVES

The example of carboplatin provided a paradigm for the development of other platinum coordination compounds with modified leaving groups. However, the antitumor

activity of these drugs generally overlap, and they are not considered effective for the treatment of cisplatin-resistant disease. Therefore, the development of platinum

analogues that produce responses in cisplatin/carboplatin-resistant tumors became necessary, and it was hypothesized that modifying the carrier ligands might

achieve this. The antitumor activity of a series of platinum compounds containing the 1,2-diaminocyclohexane (DACH) carrier ligand was initially described by

Connors et al.10 in 1972. Several of these compounds exhibited a significantly higher therapeutic index compared with cisplatin using a murine ADJ/PC6A tumor

model. Kidani et al.11 also reported significant antitumor activity of DACH platinum complexes. Burchenal and colleagues 12 selected several DACH derivatives for

preclinical development based on their activity in cisplatin-resistant murine leukemias. Subsequent in vitro studies supported the idea that DACH-based platinum

complexes were non–cross-resistant in cisplatin-resistant cell lines. 12,13 In support of these studies, Rixe et al.14 showed that DACH derivatives exhibited a unique

cytotoxicity profile compared with cisplatin and carboplatin using the National Cancer Institute 60 cell line screen. Several DACH-platinum compounds have been

tested in clinical trials; however, each has had limitations that prevented their continued use.

Interest in DACH compounds has been rekindled by the clinical development of oxaliplatin. 15 Oxaliplatin has demonstrated activity alone or in combination with

5-fluorouracil/leucovorin in colon cancer, a disease that was previously considered to be unresponsive to platinum drugs. Like cisplatin, oxaliplatin preferentially forms

adducts at the N7 position of guanine and, to a lesser extent, adenine. However, evidence suggests that the three-dimensional structure of the DNA adducts and

biological response(s) they elicit are different from that of cisplatin.

PLATINUM (IV) STRUCTURES

The octahedral stereochemistry adopted by platinum (IV) compounds has led investigators to speculate that they may exhibit a different spectrum of activity than that

of platinum (II) drugs. Two compounds that have been tested clinically without much success are ormaplatin and iproplatin. Ormaplatin was neurotoxic in phase I

trials, and iproplatin did not demonstrate activity in phase II trials. 16,17 and 18 Two platinum (IV) compounds, JM216 [bis(acetato)amminedichloro(cyclohexylamine)

platinum (IV)] and JM335 [trans-ammine(cyclohexylamine)dichlorodihydroxo platinum (IV)], have been developed in the United Kingdom and contain several unique

features.19 These compounds may also be classified as mixed amines or ammine/amine platinum (IV) complexes. JM216 is the first orally active platinum compound

and is currently undergoing phase II testing. A response rate of 38% was observed in patients with small cell lung cancer 20; however, no significant antitumor activity

was observed in patients with non–small cell lung cancer. 21 Based on the lack of antitumor activity of transplatin [ trans-diamminedichloroplatinum (II)], it has been

generally believed that most, if not all, trans platinum compounds were inactive. Renewed interest in trans compounds has occurred, however, with the observation

that JM335 and a related group of complexes exhibited significant antitumor activity in murine ADJ/PC6 and human ovarian cancer models. 19 Khokhar and

colleagues22 also have produced trans-platinum (IV) compounds containing the DACH moiety that they demonstrated to be non–cross-resistant to cisplatin.

MULTINUCLEAR PLATINUM COMPLEXES

The synthesis and preclinical studies of multinuclear platinum compounds was first reported by Farrell et al. 23 These compounds are unique in that their interaction

with DNA is considerably different from that of cisplatin, particularly in the abundance of interstrand cross-links formed. Also, the observation that multinuclear

platinum complexes containing the trans geometry exhibit antitumor activity contradicts the original dogma that platinum drugs containing the trans geometry are

inactive. Currently, the lead compound in this class of drugs is BBR3464. Its structure is described as two trans-[PtCl(NH3)2]+ units linked together by a noncovalent

tetraamine [Pt(NH3)2[H2N(CH2)6NH2]2]2+ unit. Preclinical testing of BBR3464 shows it to be significantly more potent than cisplatin and to be active in cisplatin-resistant

xenografts and p53 mutant tumors. Preliminary data from a phase I clinical trial of BBR3464 have indicated that diarrhea and myelosuppression are dose-limiting (P.

Calvert, H. Calvert, C. Sessa, G. Camboni, personal communication, 1999). In this study, a partial response was observed in a patient with metastatic pancreatic

cancer.

OTHER PLATINUM COMPLEXES

Another approach for the design of novel platinum analogues is to identify compounds that can circumvent specific cisplatin resistance mechanisms. An example of

this is ZD0473 (AMD473) [cis-amminedichloro(2-methylpyridine) platinum (II)], which is a sterically hindered platinum complex that was designed to preferentially react

with nucleic acids instead of thiol-containing molecules such as glutathione. 19 ZD0473 exhibits activity against acquired cisplatin-resistant cell lines and is active when

administered by oral or intraperitoneal routes in human ovarian cancer xenografts. 24,25 The results of a phase I clinical trial have indicated that myelosuppression is

dose-limiting and that nephrotoxicity, neuropathy, and ototoxicity are not prominent. 26 Antitumor activity was observed in previously platinum-treated head and neck

and ovarian cancer patients.

MECHANISM OF ACTION

DNA ADDUCT FORMATION

The observation by Rosenberg2 that cisplatin induces filamentous growth in bacteria without affecting RNA and protein synthesis implicated DNA as the cytotoxic

target of the drug. Evidence from several subsequent experiments supported this idea. 27,28,29,30 and 31 The differential cytotoxic effects observed with platinum drugs are

determined, in part, by the structure and relative amount of DNA adducts formed. Cisplatin and its analogues react preferentially at the N7 position of guanine and

adenine residues to form a variety of monofunctional and bifunctional adducts. 32 The first step of the reaction involves the formation of monoadducts. These

monoadducts may then react further to form intrastrand or interstrand cross-links. The predominant bidentate lesions that are formed with DNA in vitro or in cultured

cells are the d(GpG)Pt, d(ApG)Pt, and d(GpNpG)Pt intrastrand cross-links. In a study of cisplatin-treated Chinese hamster ovary (CHO) cells, these lesions were

determined to account for approximately 60%, 15%, and 20% of the total platinum DNA adducts, respectively. 33 Cisplatin also forms interstrand cross-links between

guanine residues located on opposite strands that account for less than 5% of the total DNA bound platinum. These adducts may contribute to the drug's cytotoxicity,

because they impede certain cellular processes that require the separation of both DNA strands, such as replication and transcription.

The adducts that are formed between the reaction of carboplatin with DNA in cultured cells are essentially the same as that of cisplatin. However, higher

concentrations of carboplatin are required (20- to 40-fold for cells) to obtain equivalent total platinum-DNA adduct levels because of cisplatin's slower rate of

aquation.34 The relative amounts of each lesion are different, with the d(GpNpG)Pt intrastrand adduct being the most prevalent (approximately 40%) followed by the

d(GpG)Pt (approximately 30%) and d(ApG)Pt (approximately 15%) intrastrand adducts, respectively. 33 As with cisplatin, a relatively low number of monoadducts and

interstrand cross-links are observed. The relative amounts and frequencies of the DNA adducts formed in cultured cells by oxaliplatin have also been examined.

Oxaliplatin intrastrand adducts form more slowly because of a slower rate of conversion from monoadducts; however, they are formed at similar DNA sequences and

regions as cisplatin adducts. Saris et al. 35 reported that oxaliplatin forms predominantly d(GpG)Pt and d(ApG)Pt intrastrand cross-links in vitro and in cultured cells. At

equitoxic doses, however, oxaliplatin forms fewer DNA adducts compared with cisplatin. This suggests that oxaliplatin lesions are more cytotoxic than those formed by

cisplatin.

The differences observed in cytotoxicity between the diamine (e.g., cisplatin, carboplatin) and DACH platinum compounds is not dependent on the type and relative

amounts of the adducts formed, but more likely due to the overall three-dimensional structure of the adduct and its recognition by various cellular proteins. Structural

analysis of the cisplatin d(GpG)Pt intrastrand cross-link has been accomplished by both x-ray crystallography and nuclear magnetic resonance spectroscopy. These

studies revealed that the binding of platinum to DNA causes a variety of perturbations in the double helix, including a roll of 26 to 50C between the cross-linked

guanine bases, displacement of platinum from the planes of the guanine rings, a bend of the helical axis toward the major groove, and an unwinding of the DNA. 36

Scheef et al.37 used computer modeling to demonstrate that oxaliplatin produces a similar DNA bend, base rotation, and base propeller as cisplatin. The major

difference, however, is the protrusion of the DACH moiety of oxaliplatin into the major groove of DNA, thus producing a bulkier adduct than that of cisplatin. This

bulkier, more hydrophobic adduct may be recognized differently by a host of cellular proteins involved in sensing DNA damage. 38 The functional consequence of

these effects are twofold: Proteins, such as polymerases, that recognize and participate in reactions on DNA under normal circumstances may be perturbed, whereas

processes that are controlled by proteins that recognize damaged DNA may become activated. The latter group of proteins may function in the DNA repair process or

in the initiation of programmed cell death.

PLATINUM-DNA DAMAGE–RECOGNITION PROTEINS

Several damage-recognition proteins have been identified that preferentially bind to DNA damaged by cisplatin, but not to the inactive transplatin isomer. 39,40 The first

of these to be discovered were the HMG1 (high mobility group 1) and HMG2 proteins. These proteins are capable of bending DNA as well as recognizing bent DNA

structures, such as that produced by cisplatin binding. The HMG domain, which consists of a highly basic 80 amino acid motif, has been found in other proteins, most

of which are involved in gene expression. 41 Although many theories exist as to how HMG proteins may influence cisplatin sensitivity, relationships between HMG

protein function and expression have not yet been clearly established. Recognition of platinum-DNA adducts by the mismatch repair (MMR) complex also has been

implicated in cisplatin sensitivity. 42 For example, the MSH2 (MutS homologue) and MLH1 (MutL homologue) proteins participate in the recognition of DNA adducts

formed by cisplatin.43,44 The presence of a platinum lesion results in a continuous futile cycle of repair synthesis on the DNA strand opposite the lesion, possibly

causing the accumulation of DNA strand breaks that may result in cell death. Interestingly, oxaliplatin adducts are not recognized by this MMR protein complex, which

may account for differences in the cytotoxic mechanism of the two platinum compounds.

PLATINUM DRUG–INDUCED CELL DEATH

The sequence of events that lead to cell death after the formation of platinum-DNA adducts have not yet been elucidated. However, cells treated with platinum drugs

display the biochemical and morphologic features of apoptosis. 45 These features are common to cells treated with other cytotoxic and biological agents. Therefore,

understanding the pathway(s) that are involved in the early stages of programmed cell death, including the detection/initiation and decision/commitment phases, are

important for understanding the unique activities of platinum drugs. The sensitivity of a cell to a platinum drug depends, in part, on cell cycle. For example,

proliferating cells are relatively sensitive, whereas quiescent cells or cells in G 0/G1 are relatively insensitive. 46 Thus, it is possible that programmed cell death initiated

at various cell-cycle checkpoints is governed by different proteins and signal transduction pathways.

A model for cisplatin-induced cell death in CHO cells has been provided by Sorrenson and Eastman. 47 In this study, cisplatin-treated CHO/AA8 cells experienced slow

progression through S phase and accumulated in G 2. At low drug concentrations, the cells recovered and continued to cycle. At high drug concentrations, the cells

died after a protracted G2 arrest. An aberrant mitosis was observed before apoptosis. Further studies with G 2-synchronized cells revealed that passage through S

phase is necessary for G2 arrest and cell death, suggesting that DNA replication on a damaged template may result in the accumulation of further damage, ultimately

causing the cells to die. Cisplatin-induced accumulation of human tumor cells in G 2 also has been observed in mice. Abrogating the G 2 checkpoint with pharmacologic

agents, such as caffeine or 7-hydroxystaurosporine, have been shown to enhance the cytotoxicity of cisplatin. 48 It is not yet clear how these events specifically

transduce a proapoptotic signal. However, the observations provide a valuable framework to begin to elucidate the initial steps.

The decision/commitment phase of apoptosis hinges on the balance between survival and death signals. Each cell contains a damage threshold that, once

surpassed, results in the onset of apoptosis. It is not clear what signaling pathways influence the response of cells to platinum drugs. However, it has been shown that

activators or inhibitors of known signal transduction pathways can influence platinum drug sensitivity. For example, treatment of various cell lines with tamoxifen,

epidermal growth factor, interleukin-1a, tumor necrosis factor-a bombesin, and rapamycin enhance cisplatin cytotoxicity. 49,50,51,52 and 53 Also, the expression of certain

protooncogenes, including Ha-Ras, v-abl, and Her2/neu, has been shown in some instances to promote cell survival after cisplatin exposure. 54,55,56 and 57 This is an

area of investigation that requires further study, and the overall balance of cell survival and cell death signals may be critical in determining the response of tumors to

chemotherapy.

In addition to the mounting evidence supporting the existence of programmed cell death pathways, substantial evidence indicates that cell death is influenced by

cellular signal transduction pathways such as those that control growth, differentiation, and stress response. These signals are mediated primarily by small guanosine

triphosphatases and protein serine-threonine kinases. Members of the extracellular signal-related kinase/mitogen-activated kinase family, as well as their upstream

activators, have been implicated in these events. The c-JUN amino-terminal kinase (JNK)/stress-activated protein kinase (SAPK) and p38 kinase pathways have been

shown to be activated by a variety of environmental stimuli and inflammatory cytokines. 58 JNK/SAPK and p38 phosphorylate and regulate the activity of the ATF2

(alcohol acetyltransferase II) and Elk-1 transcription factors. JNK/SAPK also phosphorylates c-JUN, a component of the AP-1 (activating protein 1) transcription factor

complex, on serine residues 63 and 73. Considerable evidence suggests that these protein kinases are involved in transmitting a drug-induced cell death signal. For

example, Zanke et al.59 demonstrated that, in mouse fibroblasts, the inhibition of JNK phosphorylation by the stable transfection of a dominant-negative

complementary DNA encoding SEK1, the protein kinase responsible for activating JNK, resulted in reduced sensitivity to cisplatin. Sanchez-Perez et al. 60 observed a

prolonged activation of JNK by cisplatin that was related to cell death. Modulating the activity of kinases upstream of JNK, including c-Abl, MKK3/MKK6, MEKK1, and

ASK1, also influences cellular drug sensitivity. 61 For example, Chen et al.62 demonstrated that overexpression of a dominant-negative ASK1, which inhibits activation

of JNK, resulted in an inhibition of cisplatin-induced apoptosis. Clearly, activation of these pathways occurs after drug exposure in some cells, and it is important to

understand the contribution of these intracellular signaling events to overall platinum drug sensitivity. Within these pathways may reside the key to understanding the

molecular basis for platinum drug–induced cell death.

MECHANISMS OF RESISTANCE

The major limitation to the successful treatment of solid tumors with platinum-based chemotherapy is the emergence of drug-resistant tumor cells. 63 Platinum drug

resistance may be intrinsic or acquired and may occur through multiple mechanisms. These mechanisms may be classified into two major groups: (1) those that limit

the formation of cytotoxic platinum-DNA adducts and (2) those that prevent cell death from occurring after platinum-DNA adduct formation. The first group of

mechanisms includes decreased drug accumulation and increased drug inactivation by cellular protein and nonprotein thiols. The second group of mechanisms

includes increased platinum-DNA adduct repair and increased platinum-DNA damage tolerance. These mechanisms have been described previously in in vitro

resistance models, and their relevance to clinical resistance is unknown ( Table 19.4-1).

TABLE 19.4-1. Correlation Coefficients Derived from the Relationships between Cisplatin-Sensitivity and Cisplatin-Resistance Mechanisms in Two Human Ovarian

Cancer Model Systems

REDUCED ACCUMULATION

The majority of cell lines that have been selected for cisplatin resistance in vitro exhibit a decreased platinum accumulation phenotype, and it is generally believed

that this is due to decreased drug uptake rather than enhanced drug efflux. Cisplatin and its analogues may accumulate within cells by passive diffusion or facilitated

transport.64 Cisplatin uptake has been shown to be nonsaturable, even up to its solubility limit, and not inhibited by structural analogues. Carrier-mediated transport is

supported by the observation that uptake is partially energy-dependent, ouabain-inhibitable, sodium-dependent, and influenced by membrane potential and cyclic

adenosine monophosphate levels. Although no specific drug transporters have been implicated in the reduced platinum accumulation phenotype, some insight into a

possible pathway has been provided. Using two different acquired cisplatin resistance model systems, Shen et al. 65 reported that the loss of the folate binding protein

(FBP) was associated with decreased cellular accumulation of cisplatin, methotrexate, arsenate, and arsenite. Although the loss of FBP was not shown to be directly

responsible for reduced cisplatin accumulation, the regulatory mechanism responsible for the reduction in FBP gene expression may be linked to the expression of a

transport protein that may influence cisplatin uptake.

The prospect of an active efflux mechanism for platinum drugs has been rekindled by the discovery of a group of multidrug resistance protein (MRP)-related transport

proteins. MRP is a member of the adenosine triphosphate–binding cassette family of transport proteins that participates in the extrusion of glutathione-coupled and

unmodified anticancer drugs out of cells. 66 Overexpression of MRP confers resistance to a variety of drugs, but not to cisplatin. For platinum complexes, the formation

of a glutathione-platinum drug conjugate may be the rate-limiting step for producing an MRP substrate. The MRP homologue cMOAT (canalicular multispecific organic

anion transporter) shares 49% amino acid sequence identity and a similar substrate specificity with that of MRP. Taniguchi et al. 67 has shown that cMOAT (MRP2) is

overexpressed in some cisplatin-resistant human cancer cell lines exhibiting a decreased platinum accumulation phenotype. These investigators also demonstrated

that transfection of an antisense cMOAT complementary DNA into HepG2 cells results in decreased cMOAT protein levels and a fivefold increase in cisplatin

sensitivity.68 Kool et al.69 examined the expression of MRP, cMOAT, and three other MRP homologues (MRP3, MRP4, MRP5) in a set of cell lines selected for

cisplatin resistance in vitro. MRP1 and MRP4 messenger RNA levels were not increased in any of the cisplatin-resistant sublines. MRP3 and MRP5 were

overexpressed in a few cell lines, but the messenger RNA levels were not associated with cisplatin resistance. In contrast, cMOAT was substantially overexpressed in

some of the cisplatin-resistant cell lines. An immunohistochemical analysis of the expression of P glycoprotein, MRP1, and MRP2 revealed that none of these

transporters was associated with response to platinum-based chemotherapy in ovarian cancer. 70

INACTIVATION

As mentioned above, the formation of conjugates between glutathione (GSH) and platinum drugs may be an important step for their inactivation and elimination from

the cell. For many years, investigators have attempted to make positive correlations between platinum drug sensitivity, GSH levels, and the relative expression of the

enzymes involved in GSH metabolism. There have been many reports showing a strong association between platinum drug sensitivity and GSH levels. 71,72,73 and 74

However, reducing intracellular GSH levels with drugs such as buthionine sulfoximine has resulted in only low to modest potentiation of cisplatin sensitivity. 75,76 Part of

the reason for this may be due to the fact that the formation of GSH-platinum conjugates is a slow process. 77 The formation of a GSH-platinum complex, however, has

been reported to occur in cultured cells, and GSH has been shown to quench platinum-DNA monoadducts in vitro, preventing them from being converted to potentially

cytotoxic cross-links.78,79 and 80 These findings raise the question of whether the intracellular reaction is catalyzed by glutathione S-transferases (GSTs). In support of

this theory, a threefold increase in cisplatin resistance was reported in CHO cells transfected with the GSTp isoenzyme. 81 In contrast, transfection of NIH3T3 cells with

GSTp resulted in hypersensitivity to cisplatin. 82 Studies attempting to associate GST activity with cisplatin sensitivity in cell lines and tumor biopsies have not

consistently shown a positive correlation between GST expression or activity and cisplatin sensitivity. 72,73 and 74,83

Inactivation of the platinum drugs may also occur through binding to the metallothionein (MT) proteins. The MTs are a family of sulfhydryl-rich, small-molecular-weight

proteins that participate in heavy metal binding and detoxication. In vitro, cisplatin binds stoichiometrically to metallothionein, and up to ten molecules of cisplatin can

be bound to one molecule of metallothionein.84 Kelley et al.85 demonstrated that overexpression of the full-length MT-IIA in mouse C127 cells conferred a fourfold

resistance to cisplatin. Furthermore, this group showed that embryonic fibroblasts isolated from MT-null mice were hypersensitive to cisplatin. 86 These studies clearly

show that modulating MT levels can alter cisplatin sensitivity. However, the contribution of MT to clinical platinum drug resistance is unclear. In some cell lines,

elevated MT levels have been shown to be associated with cisplatin resistance, whereas in others, they have not. 72,87 Studies with human tumors have shown that, in

some instances, metallothionein expression level is associated with response to chemotherapy. For example, a significant correlation between MT overexpression

and response or survival was reported in urothelial transitional cell carcinoma patients. 88 Overexpression of MT also has been observed in bladder tumors from

patients that were unsuccessful with cisplatin chemotherapy. 89

INCREASED DNA REPAIR

Once platinum-DNA adducts are formed, cells must either repair or tolerate the damage to survive. The capacity to rapidly and efficiently repair DNA damage clearly

plays a role in determining a tumor cell's sensitivity to platinum drugs and other DNA damaging agents. Evidence suggests that cell lines derived from tumors that are

unusually sensitive to cisplatin, such as testicular nonseminomatous germ cell tumors, are deficient in their ability to repair platinum-DNA adducts. 90 Increased repair

of platinum-DNA lesions in cisplatin-resistant cell lines as compared with their sensitive counterparts has been shown in several human cancer cell lines, including

ovarian,91,92 breast,93 glioma,94 and murine leukemia cell lines. 95 Evidence for increased repair of cisplatin interstrand cross-links in specific gene and nongene

regions in cisplatin-resistant cell lines also has been demonstrated. These studies have been done using a variety of in vivo methods, including unscheduled DNA

synthesis, host cell reactivation of cisplatin-damaged plasmid DNA, atomic absorption spectrometry, quantitative polymerase chain reaction, and renaturing agarose

gel electrophoresis.

The repair of platinum-DNA adducts occurs predominantly by nucleotide excision repair (NER). However, the molecular basis for the increased repair activity

observed in cisplatin-resistant cells is unknown. 96 Because the rate-limiting step in this process is platinum-adduct recognition/incision, increased expression of the

proteins that control this step are likely to enhance nucleotide excision repair activity. Using an in vitro assay, Ferry et al.97 demonstrated that the addition of the

ERCC1/XPF (excision repair) protein complex increased the platinum-DNA adduct excision activity of an ovarian cancer cell extract. Circumstantial evidence also

implicates ERCC1 expression with increased NER and cisplatin resistance. For example, expression levels of the ERCC1 and XPA genes have been shown to be

higher in malignant tissue from ovarian cancer patients resistant to platinum-based therapy compared with those responsive to treatment. 98ERCC1 expression also

has been shown to correlate with NER activity and cisplatin resistance in human ovarian cancer cells. 97 Increased levels of XPE, a putative DNA repair protein that

recognizes many DNA lesions, including platinum-DNA adducts, has been observed in tumor cell lines resistant to cisplatin. 99 It should be noted, however, that XPE is

not a necessary component for the in vitro reconstitution of NER.96,100 Increased expression of DNA polymerases a and b have been observed in cisplatin-resistant

cell lines, and increased expression of these polymerases, as well as DNA ligase, has been described in human tumors after cisplatin exposure in vivo.94 The possible

significance of these findings is unclear because the primary polymerases involved in NER are thought to be DNA polymerases d or e. 96 Although it is probably not

involved in NER, DNA polymerase b may be involved in translesion DNA synthesis. 101

Inhibiting DNA repair activity to enhance platinum drug sensitivity has been an active area of investigation. Agents that have been used include nucleoside

analogues, such as gemcitabine, fludarabine, and cytarabine; the ribonucleotide reductase inhibitor hydroxyurea; and the inhibitor of DNA polymerases a and g,

aphidicolin. All of these agents interfere with the repair synthesis stage of various repair processes, including nucleotide excision repair, and it should be noted that

these compounds are also likely to affect DNA replication and, as such, should not be strictly characterized as repair inhibitors. The potentiation of cisplatin

cytotoxicity by treatment with aphidicolin has been studied extensively in human ovarian cancer cell lines. Although some studies have demonstrated a clear

synergism with this drug combination,102,103 others have not.104 In an in vivo mouse model of human ovarian cancer, the combined treatment of cisplatin and

aphidicolin glycinate, a water-soluble form of the drug, was found to be significantly more effective than cisplatin alone. 105 The combination of cytarabine and

hydroxyurea was found to demonstrate cytotoxic synergy with cisplatin in a human colon cancer cell line 106 and in rat mammary carcinoma cell lines.107 Moreover, the

modulatory effect of cytarabine and hydroxyurea on cisplatin was associated with an increase in DNA interstrand cross-links in both cellular systems. Similarly, the

drugs gemcitabine108 and fludarabine109 have both been shown to synergize with cisplatin in causing cell death in in vitro systems, and both of these drugs have been

shown to interfere with the removal of cisplatin-DNA adducts. The likelihood of a significant improvement in the therapeutic index of cisplatin in refractory patients by

the coadministration of a repair inhibitor, however, is limited by the multifactorial nature typical of resistant tumor cells. The combination of an inhibitor of the repair

process with other modulators of resistance may be a more viable avenue in treating patients with recurrent disease. Furthermore, a modest change in drug sensitivity

may bring some refractory tumors into a range that is treatable with conventional chemotherapy.

INCREASED DNA DAMAGE TOLERANCE

Platinum-DNA damage tolerance is a phenotype that has been observed in both cisplatin-resistant cells derived from chemotherapy-refractory patients and cells

selected for primary cisplatin resistance in vitro. The contribution of this mechanism to resistance is significant, and it has been shown to correlate strongly with

cisplatin resistance as well as to resistance to other drugs in two ovarian cancer model systems (see Table 19.4-1).92,110 Like other cisplatin resistance mechanisms,

this phenotype may result from alterations in a variety of cellular pathways.

One component of DNA damage tolerance that has been observed in cisplatin-resistant cells involves the loss of function of the DNA MMR system. The main function

of the MMR system is to scan newly synthesized DNA and to remove mismatches that result from nucleotide incorporation errors made by the DNA polymerases. In

addition to causing genomic instability, it has been reported that loss of MMR is associated with low-level cisplatin resistance and that the selection of cells in culture

for resistance to this drug often yields cell lines that have lost a functional MMR system. 111 MMR deficiency may create an environment that promotes the

accumulation of mutations in drug-sensitivity genes. Another hypothesis is that the MMR system serves as a detector of platinum-DNA adducts. MSH2 alone, and in

combination with MSH6, has been shown to bind to cisplatin 1,2-d(GpG)Pt intrastrand adducts with high efficiency. 44,112 Additionally, MSH2- and MLH1-containing

protein-DNA complexes have been observed when nuclear extracts of MMR-proficient cell lines were incubated with DNA preincubated with cisplatin, but not with

oxaliplatin. These data suggest that MMR recognition of damage may trigger a programmed cell death pathway, rendering cells with intact MMR more sensitive to

DNA damage.43 Another possibility is that the cytotoxicity involves repeated rounds of synthesis past the platinum-DNA lesions followed by recognition and

subsequent removal of the newly synthesized strand by the MMR system. This futile cycling may generate DNA strand gaps and breaks that trigger programmed cell

death.113 Loss of MMR thus increases the cell's ability to tolerate platinum-DNA lesions.

Another possible tolerance mechanism related to MMR is enhanced replicative bypass, which is defined as the ability of the replication complex to synthesize DNA

past a platinum adduct.101,114 Increased replicative bypass has been shown to occur in cisplatin-resistant human ovarian cancer cells. 114 These cells are also

MMR-deficient, and it has been shown that in steady-state chain elongation assays, a 2.5- to 6.0-fold increase in replicative bypass of cisplatin adducts occurred.

Oxaliplatin adducts are not recognized by the MMR complex, and no significant differences in bypass of oxaliplatin adducts in MMR-proficient and -defective cells

were observed. DNA polymerase b, the most inaccurate of the DNA polymerases, may also function in this process. 101 The activity of this enzyme was found to be

significantly increased in cells derived from a human malignant glioma resistant to cisplatin compared with its drug-sensitive counterpart. 94

The tolerance mechanisms just mentioned are related primarily to cisplatin resistance. Because the platinum-DNA damage tolerance phenotype is often associated

with cross-resistance to other unrelated chemotherapeutic drugs, 110 the existence of a more general resistance mechanism must be considered. One possible

explanation is that the platinum-DNA damage tolerance phenotype is the result of decreased expression or inactivation of one or more components of the

programmed cell death pathway. As mentioned above in Platinum Drug–Induced Cell Death, a number of pro- and antiapoptotic signaling pathways have been

implicated in cisplatin sensitivity. The possibility exists that cells containing defective or constitutively down-regulated stress signaling pathways, such as SAPK/JNK,

may exhibit resistance to platinum drugs. A number of other proteins that regulate these pathways may also have the capacity to influence drug sensitivity. In addition,

cell death may also be influenced by expression of members of the bcl-2 gene family. This group of pro- and antiapoptotic proteins regulates mitochondrial function,

and they serve as a cell survival/cell death rheostat by forming homo- and heterodimers with one another. The antiapoptotic bcl-2 and bcl-X L proteins are localized in

the outer mitochondrial membrane and may be involved in the formation of transmembrane channels. Overexpression of bcl-2 or bcl-X L has been shown to prevent

disruption of the mitochondrial transmembrane potential and to prolong cell survival in some cells after exposure to cisplatin and other anticancer drugs. 115,116 The

activity of these proteins is negated, however, in the presence of high levels of the proapoptotic protein BAX, another bcl-2 family member. Therefore, the relative

intracellular levels of these proteins may also confer resistance to platinum drugs. An interesting connection between the bcl-2 gene family and SAPK/JNK has been

reported by Kharbanda et al.117 They found that, after genotoxic stress, SAPK/JNK is translocated to the mitochondria, where it phosphorylates bcl-X L, presumably

rendering it inactive.

CLINICAL PHARMACOLOGY

PHARMACOKINETICS

The pharmacokinetic differences observed among platinum drugs may be attributed to the structure of their leaving groups. Platinum complexes containing leaving

groups that are less easily displaced exhibit reduced plasma protein binding, longer plasma half-lives, and higher rates of renal clearance. These features are evident

in the pharmacokinetic properties of cisplatin, carboplatin, and oxaliplatin, which are summarized in Table 19.4-2. Platinum drug pharmacokinetics also have been

reviewed elsewhere.118,119 and 120

Cisplatin

After intravenous infusion, cisplatin rapidly diffuses into tissues and is covalently bound to plasma protein. More than 90% of platinum is bound to plasma protein at 4

hours postinfusion.121 The disappearance of ultrafilterable platinum is rapid and occurs in a biphasic fashion. Half-lives of 10 to 30 minutes and 0.7 to 0.8 hours have

been reported for the initial (T 1/2a) and terminal phases (T1/2g), respectively.122,123 Cisplatin excretion is dependent on renal function, which accounts for the majority of

its elimination. The percentage of platinum excreted in the urine has been reported to be between 23% and 40% at 24 hours postinfusion. 124,125 Only a small

percentage of the total platinum is excreted in the bile. 126

Carboplatin

The differences in pharmacokinetics observed between cisplatin and carboplatin depend primarily on the slower rate of conversion of carboplatin to a reactive

species. Thus, the stability of carboplatin results in a low incidence of nephrotoxicity. Carboplatin diffuses rapidly into tissues after infusion, but it is considerably more

stable in plasma. Only 24% of a dose was reported to be bound to plasma protein at 4 hours postinfusion. 127

The disappearance of platinum from plasma after short intravenous infusions of carboplatin has been reported to occur in a biphasic or triphasic manner. The initial

half-lives for total platinum, which vary considerably among several studies, are listed in Table 19.4-2. The T1/2a ranges from 12 to 98 minutes and ranges from 1.3 to

1.7 hours during the second phase (T 1/2b). Half-lives reported for the T 1/2g range from 8.2 to 40.0 hours. The disappearance of ultrafilterable platinum is biphasic, with

T1/2a and T1/2b values ranging from 7.6 to 87.0 minutes and 1.7 to 5.9 hours, respectively. Carboplatin is excreted predominantly by the kidneys, and cumulative

urinary excretion of platinum is 54% to 82%, most as unmodified carboplatin. The renal clearance of carboplatin is closely correlated with the glomerular filtration rate

(GFR).127 This observation enabled Calvert et al. 128 to design a carboplatin dosing formula based on an individual patient's GFR.

Oxaliplatin

After oxaliplatin infusion, platinum accumulates into three compartments: plasma-bound platinum, ultrafilterable platinum, and platinum associated with erythrocytes.

Approximately 85% of the total platinum is bound to plasma protein at 2 to 5 hours postinfusion. 129 Plasma elimination of total platinum and ultrafiltrates is biphasic.

The T1/2a and T1/2g are 26 minutes and 38.7 hours, respectively, for total platinum and 21 minutes and 24.2 hours, respectively, for ultrafilterable platinum (see Table

19.4-2).120 Thus, as with carboplatin, substantial differences between total and free drug kinetics are not observed. Similar to cisplatin, a prolonged retention of

oxaliplatin is observed in red blood cells. Unlike cisplatin, however, oxaliplatin does not accumulate to any significant level after multiple courses of treatment. 129 This

may explain why neurotoxicity associated with oxaliplatin is reversible. Oxaliplatin is eliminated predominantly by the kidneys, with more than 50% being excreted in

the urine at 48 hours.

PHARMACODYNAMICS

Pharmacodynamics relates pharmacokinetic indices of drug exposure to biological measures of drug effect, which is usually defined by toxicity to normal tissues or by

amount of tumor cell kill. Two issues to be addressed in such efforts are whether the effectiveness of the drug can be enhanced or the toxicity attenuated by

knowledge of the platinum pharmacokinetics in an individual. These questions are appropriate to the use of cytotoxic agents with relatively narrow therapeutic indices.

Toxicity to normal tissues can be quantitated as a continuous variable when the drug causes myelosuppression. Thus, the early studies of carboplatin demonstrated a

close relationship of changes in platelet counts to the area under the concentration-time curve (AUC) in the individual. The AUC was itself closely related to renal

function, which was determined as creatinine clearance. Based on these observations, Egorin et al. 130 and Calvert et al.128 derived formulas based on creatinine

clearance to predict either the percent change in platelet count or a target AUC. More recently, Chatelut and colleagues 131 have derived a formula that relies on serum

creatinine as well as morphometric determinants of renal function. Application of pharmacodynamically guided dosing algorithms for carboplatin has been widely

adopted as a means of avoiding overdosage (by producing acceptable nadir platelet counts) and of maximizing dose intensity in the individual. Good evidence

suggests that this approach can decrease the risk of unacceptable toxicity. Accordingly, a dosing strategy based on renal function is recommended for the use of

carboplatin.

A key question is whether maximizing carboplatin exposure in an individual can measurably increase the probability of tumor regression or survival. In an analysis by

Jodrell et al.,132 carboplatin AUC was a predictor of response, thrombocytopenia, and leukopenia. The likelihood of a tumor response increased with increasing AUC

up to a level of 5 to 7 mg × hr/mL, after which a plateau was reached. Similar results were obtained with carboplatin in combination with cyclophosphamide, and

neither response nor survival rates were determined by the carboplatin AUC in a cohort of ovarian cancer patients. 133

The relationship of pharmacokinetics to response may also be explored by investigating the cellular pharmacology of these agents. 134 As discussed above in DNA

Adduct Formation, platinum compounds form various types of DNA adducts. The formation and repair of these adducts in human cells are not easily measured. One

approach is to measure specific DNA adducts (using antibody-based assays); another is to measure total platinum bound to DNA. The formation and repair of

platinum-DNA adducts has been studied in white blood cells obtained from various groups of patients. Ma et al. 135 have reevaluated the pharmacokinetic and

pharmacodynamic interactions of cisplatin administered as a single agent. In a series of patients with head and neck cancer, they found that cisplatin exposure

(measured as the AUC) closely correlated with both the peak DNA adduct content in leukocytes and the area under the DNA-adduct–time curve. 136 These measures

were important predictors of response, both individually and in logistic regression analysis. An adaptive dosing study in which the dose of cisplatin is modified based

on DNA-adduct levels is in progress.

Based on the variability of both pharmacokinetics in individuals and of tumor genotype determinants of susceptibility to platinum agents, it seems most likely that

direct investigations of these factors will elucidate how best to use these drugs. Single-nucleotide polymorphism associations with toxicity and tumor gene expression

profiles determining susceptibility will, it is hoped, further enhance the therapeutic index by prospectively identifying sensitive and resistant populations.

FORMULATION AND ADMINISTRATION

Cisplatin

Cisplatin is administered in a chloride-containing solution intravenously over 0.5 to 2.0 hours. To minimize the risk of nephrotoxicity, patients are prehydrated with at

least 500 mL of salt-containing fluid. Immediately before cisplatin administration, mannitol (12.5 to 25.0 g) is given parenterally to maximize urine flow. A diuretic, such

as furosemide, may also be used, along with parenteral antiemetics, which currently include dexamethasone together with a 5-hydroxytryptamine 3 (5-HT3) antagonist.

A minimum of 1 L of posthydration fluid is usually given. 137 The intensity of hydration varies somewhat with the dose of cisplatin. High-dose cisplatin (up to 200 mg/m 2

per course) may be administered in a formulation containing 3% sodium chloride, but this method is no longer widely used. Cisplatin may also be administered

regionally to increase local drug exposure and to diminish side effects. Its intraperitoneal use was defined by Ozols et al. 138 and by Howell and colleagues.139

Measured drug exposure in the peritoneal cavity is some 50-fold higher than levels achieved with intravenous administration. 139 At standard doses in ovarian cancer

patients with low-volume disease, a randomized intergroup trial suggested that intraperitoneal administration is superior to intravenous cisplatin in combination with

intravenous cyclophosphamide.140 The development of combinations of carboplatin with paclitaxel has, however, superseded this technique in ovarian cancer, and the

intraperitoneal route is now infrequently used. Regional use also includes intraarterial delivery (as for hepatic tumors, melanoma, and glioblastoma), but none has

been adopted as a standard method of treatment. There is growing interest in chemoembolization for the treatment of tumors confined to the liver, and cisplatin is a

component of many popular regimens.141

Oxaliplatin

Oxaliplatin is also uncomplicated in its clinical administration. For bolus infusion, the required dose is administered in 500 mL of chloride-free diluent over a period of

2 hours. In studies of colorectal cancer, oxaliplatin has been administered as a 5-day continuous infusion, during which the dosage rate has been modified to observe

principles of chronopharmacologic administration. 145 Oxaliplatin is more frequently given as a single dose every 2 weeks (85 mg/m 2) or every 3 weeks (130 mg/m2),

alone or with other active agents. It is common to pretreat patients with active antiemetics, such as a 5-HT 3 antagonist, but the nausea is not as severe as with

cisplatin. No prehydration is required. The predominant toxicity of oxaliplatin is neurotoxicity. The development of an oropharyngeal dysesthesia, often precipitated by

exposure to cold, requires prolongation of the duration of administration to 6 hours.

Carboplatin

Cisplatin treatment over 3 to 6 hours is burdensome for clinical resources and tiring for cancer patients. Previously given as in-hospital treatment, it is now usually

administered in the outpatient setting. The exigencies of the modern health care environment have contributed to the expanding use of carboplatin as an alternative to

cisplatin, except in circumstances in which cisplatin is clearly the superior agent. Carboplatin is substantially easier to administer. Extensive hydration is not required

because of the lack of nephrotoxicity at standard doses. 142 Carboplatin is reconstituted in chloride-free solutions (unlike cisplatin, because chloride can displace the

leaving groups) and administered over 30 minutes as a rapid intravenous infusion. Carboplatin has been incorporated in high-dose chemotherapy regimens at doses

more than threefold higher than those of the standard regimens. 143 In some regimens, continuous infusion has been substituted for a rapid intravenous infusion;

however, it is doubtful that there is an advantage to this approach. Carboplatin doses up to 20 mg × min/mL may be safely administered in 200 mL of D5W over 2

hours.144

TOXICITY

A substantial body of literature documents the side effects of platinum compounds. The nephrotoxicity of cisplatin almost led to its abandonment, until Cvitkovic and

colleagues3,4 introduced aggressive hydration, which prevented the development of acute renal failure. As already noted, the toxicity of cisplatin was a driving force

both in the search for less toxic analogues and for more effective treatments for its side effects, especially nausea and vomiting. The toxicities associated with

cisplatin, carboplatin, and oxaliplatin are described in detail in the next three sections and are summarized in Table 19.4-3.

Cisplatin

The side effects associated with cisplatin (at single doses of more than 50 mg/m 2) include nausea and vomiting, nephrotoxicity, ototoxicity, neuropathy, and

myelosuppression. Rare effects include visual impairment, seizures, arrhythmias, acute ischemic vascular events, glucose intolerance, and pancreatitis. 137 The

nausea and vomiting stimulated a search for new antiemetics. These symptoms are currently best managed with 5-HT 3 antagonists and usually given with a

glucocorticoid, although other combinations of agents are still widely used. In the weeks following treatment, continuous antiemetic therapy may be required.

Nephrotoxicity is ameliorated but not completely prevented by hydration. The renal damage to both glomeruli and tubules is cumulative, and after cisplatin treatment,

serum creatinine is no longer a reliable guide to the measurement of glomerular filtration rate. An acute elevation of serum creatinine may follow a cisplatin dose, but

this index returns to normal with time. Tubule damage may be reflected in a salt-losing syndrome that also resolves with time.

Ototoxicity is a cumulative and irreversible side effect of cisplatin treatment that results from damage to the inner ear. Therefore, audiograms are recommended every

2 to 3 cycles.137 The initial audiographic manifestation is loss of high-frequency acuity (4000 to 8000 Hz). When acuity is affected in the range of speech, cisplatin

should be discontinued under most circumstances and carboplatin substituted where appropriate. Peripheral neuropathy is also cumulative, although less common

than with agents such as vinca alkaloids. This neuropathy usually is reversible, although recovery is often slow. A number of agents with the potential for protection

from neuropathy have been developed, but none is yet used widely. 146

Carboplatin

Myelosuppression, which is not usually severe with cisplatin, is the dose-limiting toxicity of carboplatin. 142 The drug is most toxic to the platelet precursors, but

neutropenia and anemia are frequently observed. The lowest platelet counts after a single dose of carboplatin are observed 17 to 21 days later, and recovery usually

occurs by day 28. The effect is dose-dependent, but individuals vary widely in their susceptibility. As shown by Egorin et al. 130 and Calvert et al.,128 the severity of

platelet toxicity is best accounted for by a measure of the drug exposure in an individual, the AUC. Both groups derived pharmacologically based formulas to predict

toxicity and guide carboplatin dosing. That of Calvert and colleagues targets a particular exposure to carboplatin:

This formula has been widely used to individualize carboplatin dosing, and it permits targeting at an acceptable level of toxicity. Patients who are elderly or have a

poor performance status or a history of extensive pretreatment have a higher risk of toxicity, even when dose is calculated with these methods, 128,130 but the safety of

drug administration has been enhanced. In the combination of carboplatin and paclitaxel, AUC-based dosing has helped to maximize the dose intensity of

carboplatin.147 Doses some 30% higher than a dosing strategy based solely on body surface area may safely be used. A determination of whether this approach to

dosing improves outcome requires a randomized trial, which is in progress.

The other toxicities of carboplatin are generally milder and better tolerated than those of cisplatin. Nausea and vomiting, although frequent, are less severe, shorter in

duration, and more easily controlled with standard antiemetics (i.e., Compazine, dexamethasone, lorazepam) than those symptoms typical after cisplatin treatment.

Renal impairment is infrequent, although alopecia is common, especially with the paclitaxel-containing combinations. Neurotoxicity is also less common than with

cisplatin, although it is observed more frequently with the increasing use of high-dose regimens. Ototoxicity is also less common.

Oxaliplatin

The dose-limiting toxicity of oxaliplatin is sensory neuropathy, a characteristic of all DACH-containing platinum derivatives. The severity of the toxicity is dramatically

less than that observed with another DACH-containing analogue, ormaplatin. This side effect takes two forms. First, a tingling of the extremities, which may also

involve the perioral region, occurs early and usually resolves within a few days. With repeated dosing, symptoms may last longer between cycles but do not appear to

be of long duration or cumulative. Laryngopharyngeal spasm and cold dysesthesias also have been reported but are not associated with significant respiratory

symptoms; they can be prevented by prolonging the duration of infusion. A second neuropathy, more typical of that seen with cisplatin, affects the extremities and

increases with repeated doses. Definitive physiologic characterization of oxaliplatin-induced neuropathy has proven difficult in large studies. Electromyograms

performed in six patients treated by Extra et al.148 revealed an axonal sensory neuropathy, but nerve conduction velocities were unchanged. Peripheral nerve biopsies

performed in this study showed decreased myelinization and replacement with collagen pockets. The neurologic effects of oxaliplatin appear to be cumulative in that

they become more pronounced and of greater duration with successive cycles. Unlike those with cisplatin, however, they are reversible with drug cessation. In a

review of 682 patient experiences, Brienza et al. 149 reported that 82% of patients who experienced grade 2 or higher neurotoxicity had their symptoms regress within 4

to 6 months. Ototoxicity is not observed with oxaliplatin. Nausea and vomiting do occur and generally respond to 5-HT 3 antagonists. Myelosuppression is uncommon

and is not severe with oxaliplatin as a single agent, but it is a feature of combinations including this drug. Oxaliplatin therapy is not associated with nephrotoxicity.