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Chapter: Basic & Clinical Pharmacology : Cancer Chemotherapy

Antifolates

Methotrexate (MTX) is a folic acid analog that binds with high affin-ity to the active catalytic site of dihydrofolate reductase (DHFR).

ANTIFOLATES

Methotrexate

Methotrexate (MTX) is a folic acid analog that binds with high affin-ity to the active catalytic site of dihydrofolate reductase (DHFR). This results in inhibition of the 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 various metabolic processes thereby 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 syn-thase (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.




Resistance to MTX has been attributed to (1) decreased drug trans-port via the reduced folate carrier or folate receptor protein,decreased formation of cytotoxic MTX polyglutamates, (3) increased levels of the target enzyme DHFR through gene amplification and other genetic mechanisms, and (4) altered DHFR protein with reduced affinity for MTX. Recent studies have suggested that decreased accumulation of drug through activation of the multidrug resistance transporter P170 glycoprotein may also result in drug resistance.

MTX is administered by the intravenous, intrathecal, or oral route. However, oral bioavailability is saturable and erratic at doses greater than 25 mg/m2. Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion. As a result, dose modification is required in the setting of renal dysfunction. Care must also be taken when MTX is used in the presence of drugs such as aspirin, nonsteroidal anti-inflam-matory agents, penicillin, and cephalosporins, as these agents inhibit the renal excretion of MTX. The biologic effects of MTX can be reversed by administration of the reduced folate leucovorin (5-formyltetrahydrofolate) or by L-leucovorin, which is the active enantiomer. Leucovorin rescue is used in conjunction with high-dose MTX therapy to rescue normal cells from undue toxicity, and it has also been used in cases of accidental drug overdose. The main adverse effects are listed in Table 54–3.


Pemetrexed

Pemetrexed is a pyrrolopyrimidine antifolate analog with activity in the S phase of the cell cycle. As in the case of MTX, it is trans-ported into the cell via the reduced folate carrier and requires activation by FPGS to yield higher polyglutamate forms. While this agent targets DHFR and enzymes involved in de novo purine nucleotide biosynthesis, its main mechanism of action is inhibition of thymidylate synthase. At present, this antifolate is approved for use in combination with cisplatin in the treatment of mesothe-lioma, as a single agent in the second-line therapy of non-small cell lung cancer, and in combination with cisplatin for the first-line treatment of non-small cell lung cancer. As with MTX, pemetrexed is mainly excreted in the urine, and dose modification is required in the setting of renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, fatigue, and hand-foot syndrome. Of note, vitamin supplementation withfolic acid and vitamin B12 appear to reduce the toxicities associated with pemetrexed, while not interfering with clinical efficacy. The hand-foot syndrome is manifested by painful erythema and swell-ing of the hands and feet, and dexamethasone treatment has been shown to be effective in reducing the incidence and severity of this toxicity.

Pralatrexate

Pralatrexate is a 10-deaza-aminopterin antifolate analog, and as in the case of MTX, it is transported into the cell via the reduced folate carrier (RFC) and requires activation by FPGS to yield higher polyglutamate forms. However, this molecule was designed to be a more potent substrate for the RFC-1 carrier protein as well as an improved substrate for FPGS. It inhibits DHFR, inhibits enzymes involved in de novo purine nucleotide biosynthesis, and also inhibits thymidylate synthase. Although pralatrexate wasoriginally developed for non-small lung cancer, it is presently approved for use in the treatment of relapsed or refractory periph-eral T-cell lymphoma. As with the other antifolate analogs, prala-trexate is mainly excreted in the urine, and dose modification is required in the setting of renal dysfunction. The main adverse effects include myelosuppression, skin rash, mucositis, diarrhea, and fatigue. Vitamin supplementation with folic acid and vitamin B12 appear to reduce the toxicities associated with pralatrexate, while not interfering with clinical efficacy.


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