Cancer chemotherapy and pharmacology
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Cancer Chemother. Pharmacol. · Jan 1994
Comparative StudyBiodistribution of O6-benzylguanine and its effectiveness against human brain tumor xenografts when given in polyethylene glycol or cremophor-EL.
O6-Benzylguanine effectively inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase in tumor cells and has been shown to increase the cytotoxicity of chloroethylnitrosoureas. This study was undertaken to ascertain the optimal vehicle for further toxicological evaluation and eventual clinical trials of O6-benzylguanine. The solubility, metabolism, bioavailability and effectiveness of O6-benzylguanine as an adjuvant therapy with BCNU were compared using two vehicles, cremophor-EL and PEG 400. ⋯ In contrast, there was a 3-fold greater amount of O6-benzylguanine in the small intestine of mice at 1 h after i.p. injection of the drug in cremophor-EL as compared with PEG 400. The rate and extent of metabolism in the liver was the same, whether the parent drug was given in PEG 400 or in cremophor-EL. These studies demonstrate that O6-benzylguanine is a more effective enhancer of the antitumor activity of BCNU when it is given in PEG 400 than when it is delivered in cremophor-EL, which may be due to a more rapid distribution of the drug to the tumor.
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Cancer Chemother. Pharmacol. · Jan 1994
Preclinical pharmacology of bizelesin, a potent bifunctional analog of the DNA-binding antibiotic CC-1065.
Bizelesin (NSC-615291), a potent, bifunctional analog of the cyclopropylpyrroloindole antitumor antibiotics CC-1065 and adozelesin, has been selected by the National Cancer Institute for evaluation as a potential chemotherapeutic agent. All three compounds bind to and alkylate DNA at the N-3 position of adenine in a sequence-selective manner. Bizelesin is unique among the analogs with bifunctional alkylating capability due to two chloromethyl moieties that are converted to the cyclopropyl alkylating species that interact with DNA. ⋯ Following i.v. administration of bizelesin (15 micrograms/kg) to male CD2F1 mice, the plasma elimination of cytotoxic activity determined with the bioassay was described by a two compartment open model; the alpha-phase (t1/2 alpha) and beta-phase (t1/2 beta) half-lives, steady-state volume of distribution (VSS), and total body clearance (ClTB) were 3.5 min, 7.3 h, 7,641 ml/kg, and 16.3 ml min-1 kg-1, respectively. The systemic drug exposure following i.p. administration was at least 10 times lower than that resulting from i.v. infusion. Following i.v. or i.p. administration the recovery of material in urine was < 0.1% of the delivered dose.