DNA Topoisomerase II Inhibitors

The podophyllotoxins are extracts of the mayapple or mandrake plant, Podophyllum peltatum, long known in folk medicine. Two glycosidic derivates, etoposide (VP-16) and teniposide (VM-26), are currently in clinical use. The main mechanism of cytotoxicity was initially ascribed to tubulin-binding properties, at sites distinct from vinca alkaloids that result in inhibition of microtubule assembly and consequent S-G2 phase block and cell death. However, new evidence demonstrates that the antimicrotubular effects occur only at concentrations severalfold higher that were not reached with clinically relevant doses. Moreover, the epipodophyllotoxins produce both single- and double-strand DNA breaks that were distinct from the cellular changes seen with antimicrotubule agents.105 Epipodophyllotoxins, and anthracyclines as well, bind to topoisomerase II, stabilize the enzyme-DNA complex (termed cleavable or cleavage complex), and inhibit the rean-nealing of the cleaved DNA, thus resulting in both single- and double-stranded DNA strands. Similar to topoisomerase I inhibitors, replication fork collision with this cleavable complex increases the degree of lethal DNA fragmentation that ultimately leads to apoptosis.

Etoposide

VP-16 is available in both intravenous and oral formulations. Mean oral bioavailability is 50%, and nonlinear at doses beyond 200 to 250mg/m2. It exhibits high plasma protein binding such that patients with low serum albumin seem to be at risk for associated toxicities. It is eliminated by both renal and hepatic mechanisms. Up to 40% of unchanged drug is cleared through the kidneys. Dose reduction is recommended in patients with impaired creatinine clearance. Administration of cisplatin before VP-16 reduces VP-16 clearance, likely secondary to the effects on cytochrome P-450. Sequence-dependent synergism and reduced myelosuppres-sion are also observed when paclitaxel administration precedes VP-16. VP-16 phosphate is a water-soluble prodrug that is completely and rapidly converted to VP-16. Its chief advantage lies in the reduced incidence of hypersensitivity reactions and better safety and tolerability profile. Pharma-cokinetic, toxicity, and antitumor activity of VP-16 apply to VP-16 phosphate. Single-agent randomized studies demon strate its marked schedule-dependent activity such that multiple daily divided-dose schedules result in higher rates of response and survival than continuous administration of the same total dose over 1 day. Antitumor activity seems to correlate with the duration of exposure above a threshold concentration; this is not seen in combination regimens.

Teniposide

VM-26 is more extensively metabolized by the liver, although its plasma clearance is slower than VP-16. It has an even higher degree of protein binding than VP-16 (99% versus 94%). Although CSF penetration is low, VM-26 is generally considered more clinically effective than VP-16 in the treatment of gliomas. Although it is only available for IV administration, this formulation may be administered orally, with a bioavailability of approximately 40%.

Noncumulative myelosuppression, chiefly neutropenia, is the principal dose-limiting toxicity of the epipodophyllo-toxins. Nausea and vomiting are the main gastrointestinal toxicities, although usually mild to moderate in severity. Mucositis may be seen with high-dose VP-16 therapy. Other side effects seen with high-dose therapy are metabolic acido-sis and reversible hepatotoxicity. Rapid infusion may result in transient hypotension. Hypersensitivity reactions, seen in less than 2% of patients receiving IV VM-26 and VP-16 but not oral VP-16, may result in part from the diluent used and occurs more frequently with rapid infusion. Incidence of secondary leukemias ranges from 0.37% to 4.7% and appears to be dose related. VP-16 is approved for use in small cell lung carcinoma and testicular carcinomas. VM-26 is used as part of the induction therapy of refractory childhood acute lym-phoblastic leukemias.

A Disquistion On The Evils Of Using Tobacco

A Disquistion On The Evils Of Using Tobacco

Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.

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