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Vindesine: relationship between toxicity and adrenocortical activation
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Vindesine: relationship between toxicity and adrenocortical activation Preziosi, P., Navarra, P., Del Carmine, R., D ' A m a t o , M., Ragazzoni, E. and Vacca *, M. Inst. of Pharmacology, Catholic University of the Sacred Heart of Rome, I.go F. Vito !, 1-00168 Roma and * Inst. Pharmacology University of Sassari, Via Rolando I, 1-07100 Sassari, italy
Anticancer drags display a strong toxicity in the absence of hypophyseal or adrenal ~ _~ecretion (Prezi-'osi et al., 1988a). On the one hand we investigated (1) mortality by videsine (desacetylvinblastine c a r ~ x ~ d e , VIN), an anticancer drug endowed with a long-lasting adrenal activation (Preziosi et al., 1988b) given as a single dose (0.1-0.5 m g / k g i.v.) to hypophysectomized (HYPOX) or adrenalectomized (ADX) adult male rats ~ d (2) the effects of replacement therapies with long-acting synthetic ACTH1.24 (LATH, 0.5 mg/kg every third day i.m) or corticosterone (B: 4 m g / k g twice daily i.m.). On the other hand, we studied the mechanism by which VIN stimulates adrenal secretion in intact rats. VIN (0.1-0.5 mg/kg, 1/20 and 1 / 4 of late LDso in the rat) provoked no deaths in intact rats within 24 days. Mortality of 100~ was observed after VIN 0.5 mg/kg in HYPOX or ADX rats. VIN (0.1 mg/kg, about the human therapeutic dose per kg) provokes 10% and 77% mortality in HYPOX and ADX rats respectively within 15 days. LATH delayed 1009~ mortality up to 6th day in HYPOX 0.5 mg/kg VIN-treated rats and halved (from 40~ to 20~ at 24th day) that observed in HYPOX 0.1 mg/kg VIN-treated animals. B had no effect on ADX rats treated with VIN 0.5 mg/kg; it strongly delayed rnorta!~ty (11.1% and 44% against 77% at 15th and 24th das" respectively) in likewise-ablated 0.1 mg/kg VIN treated rats. Thus, VIN seems more toxic in ADX than in HYPOX rats and replacement therapies more active in lower dose VIN-treated rats. The unusually strong and long-lasting (up to 60 hours) VIN-induced increase of plasma 8 dependent on pituitary ACTH was observed only after VIN 2 mg/kg i.v. corresponding to late VIN (within 24th day)-LDs0. Stimulated/basal ratio for plasma B was 20, 1.8 and 1.6 for VI?,~ 2-1 and 0.2 mg/kg i.v., respectively. In vitro VIN (10 -s - 10 -5 M) was unable to stimulate ACTH and B release from superfused isolated pituitary and adrenal fragments respectively. In pituitary-stalk-sectioned rats plasma B incyease by VIN (2 mg/kg i.v.) is lacking. In medullectomized rats the same dose of VIN provoked adrenocortical activation 28 day'~ after enucleation in absence of epinephrine (E) release, a possible stimulating agent of pituitary cort~c.otrophs. Therefore a suprahypophyseal mechanism involving the release of hypothalamic corticotrophin-releasing hormone seems to be responsible for VIN-induced adrenocortical activation. This activation, observed only for doses of 1-2 mg/kg, seems to be unrelated to the role played by the adrenals in protecting rats against mortality by VIN doses unable to stin~ulate the hypothamic-hypophyseal-adrenal axis. Supported by grants MPI 40~ 1989 to P.P., MPI 60~ 88 to M.V. and NRC of Italy 88.00827.44 1988, Target Project Oncology.
References Preziosi, P., Navarra, P., Vacca, M., 1988a, Arch. Toxicol. suppl. 12, 300. Preziosi, P., Navarra, P., Del Carmine, R., Ragazzoni, E., Vacca, M., 1988b, Pharmacol. Res. Comm. 20, suppl. 2, 316.
Vindesine: relationship between toxicity and adrenocortical activation Preziosi, P., Navarra, P., Del Carmine, R., D ' A m a t o , M., Ragazzoni, E. and Vacca *, M. Inst. of Pharmacology, Catholic University of the Sacred Heart of Rome, I.go F. Vito !, 1-00168 Roma and * Inst. Pharmacology University of Sassari, Via Rolando I, 1-07100 Sassari, italy
Anticancer drags display a strong toxicity in the absence of hypophyseal or adrenal ~ _~ecretion (Prezi-'osi et al., 1988a). On the one hand we investigated (1) mortality by videsine (desacetylvinblastine c a r ~ x ~ d e , VIN), an anticancer drug endowed with a long-lasting adrenal activation (Preziosi et al., 1988b) given as a single dose (0.1-0.5 m g / k g i.v.) to hypophysectomized (HYPOX) or adrenalectomized (ADX) adult male rats ~ d (2) the effects of replacement therapies with long-acting synthetic ACTH1.24 (LATH, 0.5 mg/kg every third day i.m) or corticosterone (B: 4 m g / k g twice daily i.m.). On the other hand, we studied the mechanism by which VIN stimulates adrenal secretion in intact rats. VIN (0.1-0.5 mg/kg, 1/20 and 1 / 4 of late LDso in the rat) provoked no deaths in intact rats within 24 days. Mortality of 100~ was observed after VIN 0.5 mg/kg in HYPOX or ADX rats. VIN (0.1 mg/kg, about the human therapeutic dose per kg) provokes 10% and 77% mortality in HYPOX and ADX rats respectively within 15 days. LATH delayed 1009~ mortality up to 6th day in HYPOX 0.5 mg/kg VIN-treated rats and halved (from 40~ to 20~ at 24th day) that observed in HYPOX 0.1 mg/kg VIN-treated animals. B had no effect on ADX rats treated with VIN 0.5 mg/kg; it strongly delayed rnorta!~ty (11.1% and 44% against 77% at 15th and 24th das" respectively) in likewise-ablated 0.1 mg/kg VIN treated rats. Thus, VIN seems more toxic in ADX than in HYPOX rats and replacement therapies more active in lower dose VIN-treated rats. The unusually strong and long-lasting (up to 60 hours) VIN-induced increase of plasma 8 dependent on pituitary ACTH was observed only after VIN 2 mg/kg i.v. corresponding to late VIN (within 24th day)-LDs0. Stimulated/basal ratio for plasma B was 20, 1.8 and 1.6 for VI?,~ 2-1 and 0.2 mg/kg i.v., respectively. In vitro VIN (10 -s - 10 -5 M) was unable to stimulate ACTH and B release from superfused isolated pituitary and adrenal fragments respectively. In pituitary-stalk-sectioned rats plasma B incyease by VIN (2 mg/kg i.v.) is lacking. In medullectomized rats the same dose of VIN provoked adrenocortical activation 28 day'~ after enucleation in absence of epinephrine (E) release, a possible stimulating agent of pituitary cort~c.otrophs. Therefore a suprahypophyseal mechanism involving the release of hypothalamic corticotrophin-releasing hormone seems to be responsible for VIN-induced adrenocortical activation. This activation, observed only for doses of 1-2 mg/kg, seems to be unrelated to the role played by the adrenals in protecting rats against mortality by VIN doses unable to stin~ulate the hypothamic-hypophyseal-adrenal axis. Supported by grants MPI 40~ 1989 to P.P., MPI 60~ 88 to M.V. and NRC of Italy 88.00827.44 1988, Target Project Oncology.
References Preziosi, P., Navarra, P., Vacca, M., 1988a, Arch. Toxicol. suppl. 12, 300. Preziosi, P., Navarra, P., Del Carmine, R., Ragazzoni, E., Vacca, M., 1988b, Pharmacol. Res. Comm. 20, suppl. 2, 316.