LABORATORY–CLINICAL INTERFACE
Pharmacology of oxaliplatin and the use of pharmacogenomics to individualize therapy

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Summary

Oxaliplatin is a relatively new platinum analogue that is currently used in pharmacotherapy of metastatic colorectal cancer. Its dose-limiting toxicity is sensory neuropathy, which can be modulated by infusion of calcium and magnesium. Oxaliplatin exerts its anti-tumour effects by platinum-adduct formation, binding to cellular proteins and possibly interfering with RNA synthesis as well. If they are not removed from DNA, oxaliplatin adducts are lethal. Cellular defense mechanisms prevent adduct formation (e.g., glutathione-S-transferase) or remove DNA adducts (e.g., nucleotide excision repair). Depending on the activity of necessary enzymes in these cellular defense pathways, oxaliplatin induced damage varies from one individual to another.

There is growing evidence that polymorphisms in genes coding for DNA repair enzymes and metabolic inactivation routes contribute to the interindividual differences in anti-tumour efficacy and toxicity of oxaliplatin. Single nucleotide polymorphisms (SNPs) may yield inactive enzymes, or increased gene transcription and hence increased enzyme production. This review covers findings of recent investigations on the associations of SNPs and clinical outcome after oxaliplatin chemotherapy in metastatic colorectal cancer.

Introduction

Oxaliplatin (Eloxatin®) is a relatively new platinum analogue that has been licensed in the European Union since 1999, and in the United States since 2002. The drug is currently applied in new promising chemotherapeutic regimens in the treatment of advanced colorectal cancer.

The first platinum analogue cisplatin (Platinol®) was described in 1844 as Peyrone’s chloride. Its cytotoxic properties were unrecognized until 1965 when Rosenberg and his colleagues observed inhibition of bacterial growth by an electric current. Later it appeared that this phenomenon was due to the formation of cytotoxic compounds, e.g., cisplatin in an ammonia buffer around the platinum electrode and not attributable to direct effects of the electric current itself.1

Cisplatin was investigated in several clinical trials in the early 1970s and became available for clinical use in 1978. Cisplatin has little effect on colorectal cancer but it changed the prognosis for ovarian and especially for testicular cancer patients to a great extent. However, cisplatin causes severe side effects of which renal toxicity and peripheral neuropathy are dose-limiting. Renal toxicity caused by cisplatin is clinically manifested by elevation of blood urea nitrogen, serum creatinine and electrolyte disturbances (e.g., hypomagnesemia). Adequate intravenous hydration, slow cisplatin infusion rates and simultaneous administration of mannitol are applied to circumvent renal toxicity. Cisplatin has a high emetogenic potential but its gastrointestinal side effects such as nausea and vomiting can be effectively controlled by administration of dopamine agonists, corticosteroids and especially serotonin antagonists, alone or in combination. In contrast, ototoxicity and neurotoxicity by cisplatin are difficult to control and quite often a reason to stop treatment or reduce dose. Ototoxicity is characterized by tinnitus (often reversible) and hearing loss (irreversible), especially in the high-frequency range. Its severity is usually related to the cumulative dose received in subsequent therapeutic courses. Neurotoxicity involves peripheral neuropathy of the upper and lower limbs, including paresthesias, weakness, tremors and loss of taste.1

In an attempt to overcome the renal and gastrointestinal side effects of cisplatin, less toxic platinum analogues were developed and as a result, carboplatin has replaced cisplatin in many chemotherapeutic regimens. Carboplatin has a different spectrum of toxicity, as its primary toxic effects are haematological.2 Novel platinum compounds are still being tested (e.g., the orally effective satraplatin) and others, such as nedaplatin and oxaliplatin, have recently been approved. Interestingly, oxaliplatin shows no inheritant cross resistance with both cisplatin and carboplatin. This is especially relevant for the treatment of colorectal cancer, a disease that is known to be extremely insensitive to the earlier platinum analogues. At the same time the toxicity profile of oxaliplatin is favourable, with frequencies for ototoxicity of <1% and for renal toxicity <3%, except for unusual toxicity with regard to peripheral sensory nerves. Sensory neuropathy usually arises during infusion, affects hands, feet and the perioral area and is enhanced by cold. These effects appear to be cumulative and they generally reverse within 4–6 months after treatment discontinuation.3

Sensory neuropathy affects about 85–95% of all patients. An explanation for this unusual high incidence is proposed by Grolleau et al.4 Chelation of calcium ions by the oxalate group was suggested to block the voltage-gated sodium channels of sensory neurons, producing acute toxicity to the neuron, and in the long term inducing neuropathy. Indeed, infusion with calcium and magnesium salts significantly reduced the incidence of sensory neurotoxicity in patients with advanced colorectal cancer without affecting tumour response.5 Only five of 69 patients (7%) receiving calcium/magnesium infusions experienced distal paresthesias, whereas these adverse events were reported for 17 of 65 patients (26%) in the control group. McKeage suggests an alternative mechanism for oxaliplatin induced neurotoxicity assuming that oxaliplatin inhibits rRNA synthesis in ganglionic sensory nerves, causing damage to sensory nerve nucleoli.6 Peripheral neuropathy, diarrhoea and leucopenia can be modulated by using a dose schedule based on circadian rhythm (chronopharmacology or chronomodulation).7 Time-dependent dosage is effective in limiting gastrointestinal and neurological toxicities, and at the same time anti-tumour activity is increased compared to continuous infusion of oxaliplatin. Research indicates that, although scarcely used, chronomodulation is not a unique feature of oxaliplatin, and that cisplatin and carboplatin adverse effects can be modulated in the same manner.[8], [9] However, due to its complexity and for practical reasons chronopharmacology of oxaliplatin has only been used by a selected number of specialized medical facilities.

The US Food and Drug Administration (FDA) have now approved oxaliplatin for treatment of metastatic colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin (LV). Patients receiving oxaliplatin should have experienced recurrence or progression of metastatic disease within 6 months of completion of first-line 5-FU/LV + irinotecan combined therapy. Although grade 3 and 4 haematopoietic and gastrointestinal toxicity is limited for 5-FU monotherapy, combined administration with oxaliplatin significantly increases the incidence of thrombocytopenia, neutropenia, diarrhoea and nausea.10 Oxaliplatin combination therapy (85 mg/m2 every 2 weeks or 130 mg/m2 every 3 weeks) has a twofold higher response rate compared to 5-FU/LV therapies and also improves progression free survival (PFS) in chemotherapy-naive patients11 (Table 1). In addition, patients who underwent curative resection of stage II or III colon tumours had 23% less chance of relapse within 3 years if they had received 5-FU/LV + oxaliplatin compared to 5-FU/LV alone as adjuvant treatment.12

The efficacy of oxaliplatin in combination with 5-FU/LV was compared to 5-FU/LV or oxaliplatin monotherapy in metastatic colorectal cancer patients who experienced relapse or progression within 6 months of first-line therapy. At interim analysis, patients with the combination regimen had a significantly higher response rate and longer median time to progression (9.9%, 4.6 months) compared to 5-FU/LV (0%, p = 0.0002, 2.7 months) and oxaliplatin alone (1%, 1.6 months). The most frequent grade 3 and 4 side effects for patients receiving combination therapy were neutropenia (44%), neuropathy (7%), nausea (11%), vomiting (9%) and diarrhoea (11%).10 A randomized multicenter trial demonstrated that a regimen consisting of 5-FU/LV and oxaliplatin was more effective and better tolerated than the topo-isomerase I inhibitor irinotecan in combination with oxaliplatin, or than irinotecan with 5-FU/LV. Survival rate was significantly lower for the 5-FU/LV/irinotecan regimen and response rate was significantly higher for 5-FU/LV/oxaliplatin (45%) compared to oxaliplatin/irinotecan (35%, p = 0.03) and 5-FU/LV/irinotecan (31%, p = 0.002) combinations.13

Although response rates shown in various clinical trials vary depending on patient selection and concomitant therapy, it is clear that oxaliplatin is a promising new agent in the scarce armamentarium of drugs available for the treatment of metastatic colorectal cancer. However, the clinical efficacy and toxicity for the individual patient are still largely unpredictable, and at the start of chemotherapy it is unclear which chemotherapeutic regimen the individual patient will benefit most from. Objective response rates for various chemotherapeutic regimens range from 10% to 50%.

For some other drugs, such as antiepileptics and antibiotics, patient outcome can be described by pharmacokinetic and/or pharmacodynamic modelling, based on measurements of the drug in blood or other body fluids. For example, phenytoin serum levels are monitored in epileptic patients, as they are useful for predicting efficacy and toxicity in the individual patient. Unfortunately, for anti-tumour therapy there are generally no such simple concentration–effect relationships14 and clinical efficacy depends upon a diversity of factors, including inherited and acquired drug resistance of tumour tissue or host body.

In addition to classical therapeutic drug monitoring15 the newly evolving field of pharmacogenetics advocates drug choice taking into account genetic differences among patients and/or tumours. Pharmacogenetics gives us more insight into clinically relevant issues of response diversity, and will therefore most likely change the management of cancer therapy in the future.16

In this manuscript the pharmacogenetics relevant to oxaliplatin chemotherapy are reviewed. After a brief introduction on the pharmacology of oxaliplatin, genetic polymorphisms in genes coding for DNA-repair, biotransformation and colorectal tumour response are discussed and their impact on clinical outcome is reviewed. This information gives detailed insight into (experimental) approaches on how to individualize oxaliplatin-based chemotherapy in colorectal cancer aiming at increasing drug efficacy while minimizing chemotherapy-induced toxicity.

Section snippets

Pharmacokinetics

The oxaliplatin molecular structure consists of a central platinum atom (Pt), surrounded by a 1,2-diaminocyclohexane group (DACH) and a bidentate oxalate ligand (Fig. 1). Due to its DACH ligand, stereochemical isomers of the oxalate–Pt–DACH complex exist, of which the trans-1-(R,R)–DACH–Pt isomer (oxaliplatin) was shown to be the most cytotoxic.7

Oxaliplatin shows similar chemical behaviour and has a comparable mechanism of action as compared to the other platinum derivatives. First, the

Pharmacodynamics

The cytotoxic activity of oxaliplatin is initiated by formation of a DNA adduct between the aquated oxaliplatin derivative and a DNA base. Initially, only monoadducts are formed but eventually oxaliplatin attaches simultaneously to two different nucleotide bases resulting in DNA cross-links. Compared to cisplatin, this conversion takes more time, but in vitro the two-step process is generally completed in about 15 min.3

The adducts are formed with the N-7 positions of guanine and adenine

Pharmacogenetics

Several mechanisms are described that confer decreased sensitivity or resistance to oxaliplatin, including diminished cellular drug accumulation, increased intracellular drug detoxification and increased Pt–DNA adduct repair (Table 2).

The uptake of platinum by cells is not completely understood but there is evidence that decreased accumulation is the most common mechanism of resistance to cisplatin. Comparable observations are described for oxaliplatin resistant cell lines.26 Platinum uptake by

DNA repair polymorphisms

Since the primary anti-tumour mechanism of oxaliplatin is the formation of Pt–DNA adducts (ultimately leading to cell cycle arrest and apoptosis), polymorphisms in genes involving the repair of these adducts, such as nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and other post-replicative repair pathways (Table 2), may affect oxaliplatin efficacy.

Glutathione-S-transferase

Polymorphisms associated with cellular platinum drug clearance affect oxaliplatin efficacy by lowering intracellular concentrations of the drug. This so-called cellular detoxification is the result of conjugation of Pt drug to biomolecules such as methionine, cysteine and glutathione (Fig. 2). The latter conjugation is catalyzed by the glutathione-S-transferase enzyme (GST). The conjugation of toxic and carcinogenic electrophilic molecules with glutathione by GST is followed by cellular

Discussion

Pharmacogenetics sheds new light on the classical pharmacological question and understanding why individuals respond differently to various drug treatments. Current anti-cancer drug treatments are effective in only a minority of patients and it is not yet possible to reliably predict which patient benefits from a certain chemotherapeutic drug treatment or which patient will experience (life-threatening) drug toxicity. Pharmacogenetics is aiming at individuating drug therapy thereby increasing

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