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. A reverse-phase high-performance liquid chromatography (HPLC) assay and an L1210 cell bioassay were developed for bizelesin and subsequently applied to stability and murine pharmacokinetics studies. Following 48 h of incubation with L1210 cells the 50% growth-inhibitory concentrations (IC₅₀) of bizelesin, adozelesin, and CC-1065 were 2.3, 3.4, and 88.1 p M, respectively. Bizelesin was stable in organic solvents but was less stable in aqueous solutions, with the half-life values obtained in buffers at pH 4, 7, and 10 being 9.6, 2.1, and <1 h, respectively. By HPLC analysis, bizelesin degradation was associated with the appearance of two peaks, the mono- and dicyclopropyl derivatives formed by base-catalyzed intramolecular alkylation of the chloromethyl groups. Bizelesin and the dicyclopropyl derivative were equipotent in the L1210 cell bioassay. Following i.v. administration of bizelesin (15 μg/kg) to male CD2F₁ mice, the plasma elimination of cytotoxic activity determined with the bioassay was described by a two compartment open model; the α-phase (t_1/2α) and β-phase (t_1/2β) half-lives, steady-state volume of distribution (V_SS), and total body clearance (Cl_TB) 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.