Possible mechanism of the selectivity of the cytostatic action of antineoplastic preparations

A model of the phenomenon of selectivity of antineoplastic phase-specific preparations in leukemia, based on the assumption that any proliferating cells are equally sensitive to the action of such preparations, is suggested. Therefore, selectivity, the concept and fundamental significance of which were formulated and substantiated by the authors earlier, can be expressed in terms of the proliferative pathways of the normal and leukemic populations, the ratio between which thus plays the deciding role in the selection of the optimum system of therapy. The concept of maximum selectivity, which is a convenient numerical characteristic of a preparation, was introduced. A comparative quantitative analysis was made of a number of antineoplastic preparations (vinblastine, vincristine, amethopterin, arabinosylcytosine, azaserine); it showed that the conclusions of the model do not contradict the experimental data.     

Role of the adrenal glands in the cytostatic action mechanism of antitumor antibiotics

The state of the steroidogenic function of the adrenal glands, lipid spectrum of the adrenal gland tissue and metabolism rate of 11-oxycorticosteroids (11-OCS) in the liver tissue and their levels in the blood plasma were studied on rats after a single administration of karminomycin in a dose of LD50 (1.55 mg/kg). The hormones of the adrenal cortex were shown to play a definite role in the mechanism of the karminomycin damaging effect. Dependence of the changes on the time of the drug effect was noted. The shifts were of a reversible character. No direct toxic damages in the tissue of the adrenal glands were observed. Only an increase in the 11-OCS blood levels and a decrease in the steroid metabolism in the liver tissue were shown. The latter must be due to the direct cytotoxic effect of karminomycin on the tissue of this organ.     

Studies on the mechanism of action of the aromatase inhibitor, 4-hydroxyandrostenedione

[1 beta-3H], [1 alpha,2 alpha-3H] and [1 beta,2 beta-3H] 4-Hydroxyandrostenedione (4-OH-A) were synthesized to study the mechanism of inhibition of aromatase by 4-OH-A. Incubations of [1 beta-3H] and [1 beta,2 beta-3H] 4-OH-A with placental microsomes in the presence of NADPH showed very little loss of tritium, with aromatization of 4-OH-A ranging from 0.3 to 0.6 percent. No loss of tritium was observed in the absence of NADPH. The extent of covalent binding of 4-OH-A to microsomal proteins was higher with incubations in the absence of NADPH than with those in the presence of NADPH. These results are discussed in light of what has been proposed for the mechanism of androgen aromatization.     

Studies on the mechanism of action of xanthine oxidase

Recent studies of the reaction mechanism of the molybdenum-containing enzyme xanthine oxidase are presented. The pH-dependence of both the steady-state and rapid reaction kinetics of the enzyme exhibits is bell-shaped, with pK(a)s for the acid and alkaline limbs of 6.6 and 7.4, respectively. These are assigned to ionizations of an active site base and substrate, respectively, with the implication that enzyme acts on the neutral rather than monoanionic form of the purine substrate. A computational study provides evidence that in the course of the reaction tautomerization of substrate occurs, with a proton moving from N-3 to N-9 in the course of the reaction - enzyme facilitation of this tautomerization may contribute as much as 24 kcal/mol in transition state stabilization for the reaction. Electron spin echo (ESEEM) and electron-nuclear double resonance (ENDOR) studies of the so-called "very rapid" Mo(V) intermediate of the reaction, the latter work using a newly synthesized form of the substrate 2-hydroxy-6-methylpurine that has been selectively isotopically labeled at C-8, indicates that product is bound to the molybdenum of the active site in a simple, end-on fashion, consistent with a reaction mechanism involving nucleophilic attack of a (deprotonated) Mo-OH on the C-8 position of substrate. A kinetic study using a series of purines has failed to identify a correlation between the one-electron reduction potential for substrate and catalytic effectiveness, indicating that a reaction mechanism initiated by one-electron, outer-sphere electron transfer is unlikely. Finally, a consideration of the active site structure in the context of the above work suggests specific amino acid residues to target for site-directed mutagenesis studies. Preliminary experiments with two such mutants are entirely consistent with the proposed catalytic roles of two active site glutamate residues.     

Studies on the mechanism of the vasodilator action of nicorandil

Nicorandil, a compound having structural similarities to some of the organic nitrates, was studied for its mechanism of vasodilation. Nicorandil is thought to be a K+ channel opening agent. However, little is known about its receptor activation profile, its endothelial dependence, and its effects in atherosclerotic vessels. Nicorandil, at 0.2 to 5 x 10(-6) M, relaxed norepinephrine precontracted rabbit aortic rings in a concentration-dependent manner. Moreover, nicorandil relaxed aortic rings to the same extent in the presence and absence of an intact endothelium. However, nicorandil's effect was diminished in aortic rings from atherosclerotic rabbits. The vasorelaxation action of nicorandil was unaffected by the cyclooxygenase inhibitor ibuprofen or the lipoxygenase inhibitor propyl gallate, suggesting that nicorandil does not act via the release of a vasodilator eicosanoid. Although the nicorandil effect was not influenced by atropine, a muscarinic receptor antagonist, it was significantly attenuated by methylene blue, a guanyl cyclase inhibitor. Thus, nicorandil has some properties in common with organic nitrates and with K+ channel activators but appears to be a unique type of vasodilator.