Epipodophyllotoxins

Two of the many semisynthetic derivatives of podophyllotoxins show significant therapeutic activity in several human neoplasms, including pediatric leukemia, small cell carcinomas of the lung, testicular tumors, Hodgkin's disease, and large cell lymphomas. These derivatives, etoposide (VP-16-213) and teniposide (VM-26), have no effect on microtubular structure or function at usual concentrations even though podophyllotoxin binds to tubulin at a site distinct from that for interaction with the vinca alkaloids. Etoposide and teniposide have similar mechanisms of action and activities against different tumors. Unlike podophyllotoxin, but like the anthracyclines, they form a ternary complex with topoisomerase II and DNA and prevent resealing of the break that normally follows topoisomerase binding to DNA. The enzyme remains bound to the free end of the broken DNA strand, leading to an accumulation of DNA breaks and cell death. Cells in the S and G2 phases of the cell cycle are most sensitive to etoposide and teniposide. Resistant cells demonstrate amplification of the gene that encodes the P-glycoprotein, mutation or decreased expression of topoiso-merase II, or mutations of the p53 tumor suppressor gene.

Etoposide

Oral administration of etoposide results in variable absorption that averages ~50%. After intravenous injection, peak plasma concentrations of 30 jlg/mL are achieved; there is a biphasic clearance with a terminal t122 of ~6-8 hours in patients with normal renal function. Approximately 40% of an administered dose is excreted intact in the urine. In patients with compromised renal function, dosage should be reduced in proportion to the reduction in creatinine clearance. In patients with advanced liver disease, low serum albumin and elevated bilirubin (which displaces etoposide from albumin) increase the unbound fraction of drug, increasing the toxicity of any given dose. However, guidelines for dose reduction in this circumstance have not been defined. Drug concentrations in the CSF average 1—10% of those in plasma.

The intravenous dose of etoposide (vepesid, toposar, etopophos) in combination therapy for testicular cancer is 50—100 mg/m2 for 5 days, or 100 mg/m2 on alternate days for 3 doses. For small cell carcinoma of the lung, the dose in combination therapy is 50—120 mg/m2/day intravenously for 3 days, or 50 mg/day orally for 21 days. Cycles of therapy usually are repeated every 3-4 weeks. When given intravenously, the drug should be administered slowly during a 30-60-minute infusion to avoid hypotension and bronchospasm, which likely result from the additives used to dissolve etoposide.

A disturbing complication of etoposide therapy is the development of an unusual form of acute nonlymphocytic leukemia with a translocation in chromosome 11 at 11q23. This locus contains the MLL or mixed-lineage leukemia gene that regulates the proliferation of pluripotent stem cells. The leukemic cells have the cytological appearance of acute monocytic or monomyelocytic leukemia. Another distinguishing feature of etoposide-related leukemia is the short time interval between the end of treatment and onset of leukemia (1-3 years), as compared to the 4-5-year interval for secondary leukemias related to alkylating agents, and the absence of a myelodysplastic period preceding leukemia. patients receiving weekly or twice-weekly doses of etoposide, with cumulative doses above 2000 mg/m2, seem to be at higher risk of leukemia.

Etoposide is used primarily for treatment of testicular tumors, in combination with bleomycin and cisplatin, and in combination with cisplatin and ifosfamide for small cell carcinoma of the lung. It also is active against non-Hodgkin's lymphomas, acute nonlymphocytic leukemia, and Kaposi's sarcoma associated with AIDS. Etoposide has a favorable toxicity profile for dose escalation in that its primary acute toxicity is myelosuppression. In combination with ifosfamide and carboplatin, it is frequently used for high-dose chemotherapy in total doses of 1500-2000 mg/m2. The dose-limiting toxicity of etoposide is leukopenia, with a nadir at 10-14 days and recovery by 3 weeks. Thrombocytopenia occurs less often and usually is not severe. Nausea, vomiting, stomatitis, and diarrhea occur in ~15% of patients treated intravenously and in ~55% of patients who receive the drug orally. Alopecia is common but reversible. Fever, phlebitis, dermatitis, and allergic reactions including anaphylaxis have been observed. Hepatic toxicity is particularly evident after high-dose treatment. For both etoposide and teniposide, toxicity is increased in patients with decreased serum albumin, an effect related to decreased protein binding of the drug.

Teniposide

Teniposide (vumon) is administered intravenously. It has a multiphasic pattern of clearance from plasma. After distribution, half-lives of 4 hours and 10-40 hours are observed. Approximately 45% of the drug is excreted in the urine, but in contrast to etoposide, as much as 80% is recovered as metabolites. Anticonvulsants such as phenytoin increase the hepatic metabolism of teni-poside and reduce systemic exposure. Dosage need not be reduced for patients with impaired renal function. Less than 1% of the drug crosses the blood-brain barrier. However, teniposide has produced responses in small cell and non-small cell lung cancer metastases in the brain. Tenipo-side is available for treatment of refractory ALL in children and appears to be synergistic with cytarabine. It is administered by intravenous infusion in doses that range from 50 mg/m2/day for 5 days to 165 mg/m2/day twice weekly. The spectrum of activity includes acute leukemia in children, particularly monocytic leukemia in infants, as well as glioblastoma, neuroblastoma, and brain metastases from small cell carcinomas of the lung. Myelosuppression, nausea, and vomiting are its primary toxic effects.

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