Carboplatin is a second-generation platinum analog whose mechanisms of cytotoxic action, mechanisms of resistance, and clinical pharmacology are identical to those described for cisplatin. As with cisplatin, carboplatin has broad-spectrum activity against a wide range of solid tumors. However, in contrast to cisplatin, it exhibits significantly less renal and gastrointestinal toxicity. Its main dose-limiting toxicity is myelosuppression. It has, therefore, been widely used in transplant regimens to treat refractory hematologic malignancies. Moreover, since vigorous intravenous hydration is not required for carboplatin therapy, carboplatin is viewed as an easier agent to administer to patients, and as such, it has replaced cisplatin in various combination chemotherapy regimens.
Oxaliplatin is a third-generation diaminocyclohexane platinum analog. Its mechanism of action and clinical pharmacology are identical to those of cisplatin and carboplatin. However, tumors that are resistant to cisplatin or carboplatin on the basis of mismatch repair defects are not cross-resistant to oxaliplatin, and this finding may explain the clinical activity of this platinum compound in colorectal cancer. Oxaliplatin was initially approved for use as second-line therapy in combination with the fluoropyrimidine 5-fluorouracil (5-FU) and leucovorin, termed the FOLFOX regimen, for metastatic colorectal cancer. There are various iterations of the FOLFOX regimen, which have now become the most widely used combinations in the first-line treatment of advanced colorectal cancer. This regimen also plays a major role in the adjuvant therapy of stage III colon cancer and high-risk stage II colon cancer. Clinical activity has also been observed in other gastrointestinal cancers, such as pancreatic, gastroesophageal, and hepatocellular cancer. Neurotoxicity is the main dose-limiting toxicity, and it is manifested by a peripheral sensory neuropathy. There are two forms of neurotoxicity, an acute form that is often triggered and worsened by exposure to cold, and a chronic form that is dose-dependent. Although the chronic form of oxaliplatin toxicity is dependent on the cumulative dose of drug administered, it tends to be more readily reversible than that observed with cisplatin-induced neurotoxicity.
The antimetabolites represent an important class of agents that have been rationally designed and synthesized based on knowledge of critical cellular processes involved in DNA biosynthesis. The individual antimetabolites and their respective clinical spectrum and toxicities are presented in Table 54–3 and are discussed below.
Methotrexate (MTX) is a folic acid analog that binds with high affinity to the active catalytic site of dihydrofolate reductase (DHFR). This results in inhibition of synthesis of tetrahydrofolate (THF), the key one-carbon carrier for enzymatic processes involved in de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine. Inhibition of these metabolic processes interferes with the formation of DNA, RNA, and key cellular proteins (see Figure 33–3). Intracellular formation of polyglutamate metabolites, with the addition of up to 5–7 glutamate residues, is critically important for the therapeutic action of MTX, and this process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS). MTX polyglutamates are selectively retained within cancer cells, and they display increased inhibitory effects on enzymes involved in de novo purine nucleotide and thymidylate biosynthesis, making them important determinants of MTX’s cytotoxic action.