Yx'-n oxaliplatin figure 2.4. Structures of the platinum analogues.
cis configuration of platinum in its +2 oxidation state, designated as Pt(II). The cis isomers are cytotoxic whereas the trans isomers are much less potent. In addition to the oxidation state and isomeric configuration, clinical activity and toxic-ity of the platinum analogues seem to be related to the type of carrier ligand and leaving groups attached to the core cis-platinum structure. As shown in Figure 2.4, carboplatin differs from cisplatin by its cyclobutane dicarboxy leaving group, whereas oxaliplatin differs from carboplatin by its 1,2-diaminocyclohexane ring as its carrier ligand. Cisplatin undergoes an aquation reaction intracellularly wherein the chloride ions (the leaving groups) are displaced because of low intracellular chloride concentration. This reaction yields mono- and di-aquo platinum complexes that form strong covalent bonds with RNA as well as DNA and protein (in descending order of affinity), with intrastrand DNA crosslinks (also termed DNA adducts) being correlated with cytotoxicity and clinical outcomes.47,48 In the case of cisplatin, detection of cisplatin-induced DNA adducts initiates a nucleotide excision DNA repair pathway (NER) as well as a signaling cascade that results in apoptosis mediated by the mismatch repair proteins (MMR). Consequently, increased NER or defective MMR protein is associated with resistance.
All three compounds are primarily cleared by the kidneys, although the extent of this clearance as well as their toxicity profiles differ. Platinum compounds, particularly cisplatin, appear to inhibit cytochrome P-450 activity, which may account for drug interactions in combination regimens with other chemotherapeutic agents. Cisplatin is generally administered with forced saline diuresis, as nephrotoxicity is dose limiting and cumulative. Its high emetogenic potential also warrants the maintenance of adequate fluid hydration.
Nephrotoxicity is manifested early as potassium and magnesium wasting, in addition to a reduction in glomerular filtration rate. The electrolyte derangements may be ascribed to inhibition of the Na+/K+ ATPase activity as well as the Ca2+ channel in renal tubular tissue.49,50 Morphologic kidney damage is greatest in the renal tubules. Peripheral neuropathy, predominantly sensory, also commonly ensues after repeated administration and often may be irreversible. Approximately 85% of patients suffer this complication when cumulative dose exceeds 300 mg/m2.51 Cumulative and dose-dependent irreversible ototoxicity is not unusual. It is used as first-line agent in treating various malignancies, such as germ cell tumor, head and neck cancers, lung cancers, osteogenic sarcoma, genitourinary neoplasms, and upper gastrointestinal (GI) malignancies.52
Carboplatin is 100 times less reactive than cisplatin in undergoing the intracellular aquation reaction. It requires 10-fold-higher drug concentrations and 7.5-fold-longer incubation time than cisplatin to induce the same degree of DNA damage. Unlike cisplatin, carboplatin is not significantly secreted by renal tubules. Its clearance is linearly related to the glomerular filtration rate (GFR). There is a good correlation between its AUC and dose-limiting thrombocytopenia. The AUC is the ratio of the amount of a drug that reaches the systemic circulation and the clearance of the drug. As car-boplatin excretion has relatively simple pharmacokinetics, a formula relating the dose to AUC and renal function has been established. Calvert's formula [carboplatin dose (mg) = target AUC (mg/mL x min) x GFR (mL/min) + 25] uses the AUC and creatinine clearance to derive dose levels. Target AUC values of 5 and 7 mg/mL x minute are recommended for single-agent carboplatin in previously treated and untreated patients, respectively. The efficacy of carboplatin appears to be suboptimal at AUCs below 5 mg/mL x min and appears to plateau above an AUC of 7.5 mg/mL x minute. It is less emetogenic and neurotoxic than cisplatin, although more myelosuppressive.
As suggested previously, there is cross-reactivity between cisplatin and carboplatin and thus a similar reaction may be seen when one analogue is substituted for another. Carbo-platin has confirmed activity for many of the diseases that are treated with cisplatin. It is of clinically equivalent efficacy as cisplatin in the treatment of non-small cell lung cancer (NSCLC), extensive-stage SCLC, and suboptimally debulked ovarian cancer. Cisplatin is clinically superior in treating germ cell, head and neck, and esophageal cancers.52
Oxaliplatin is a third-generation platinum compound that undergoes spontaneous nonenzymatic conversion to its active metabolite. Oxaliplatin differs from both cisplatin and carboplatin by its unique carrier ligand, which is thought to cause reduced recognition and repair of oxaliplatin-DNA adducts.53 It produces inter- and intrastrand DNA crosslinks more rapidly than cisplatin. It demonstrates both in vitro and in vivo activity against various tumor cell lines, even those resistant to cisplatin and carboplatin.54 Although defects in certain MMR proteins, such as those seen in colorectal cancers, lead to cisplatin resistance, this is not the case with oxaliplatin, which remains effective. Oxaliplatin is synergis-tic with fluorouracil (5-FU)/leucovorin in vitro, and its activity in vivo is significantly enhanced by combination with 5-FU. It is not nephrotoxic and has minimal hematologic, auditory, or cardiac toxicity. Certain toxicities are unique to oxaliplatin. Neurotoxicity, chiefly sensory neuropathy, is exacerbated or triggered by exposure to cold. Although dose limiting, this effect is generally reversible on discontinuation of oxaliplatin. Acute dysesthesias in the upper extremities and laryngopharyngeal region with episodes of difficulty breathing or swallowing may be observed within hours or the first few days after therapy. Diarrhea is more marked with combination chemotherapy, usually given in the regimen with 5-FU and leucovorin in metastatic colon cancer.
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