Effects of KR-30035, a novel multidrug-resistance modulator, on the cardiovascular system of rats in vivo and on the cell cycle of human cancer cells in vitro.
Anticancer Drugs
; 11(1): 55-61, 2000 Jan.
Article
em En
| MEDLINE
| ID: mdl-10757564
ABSTRACT
The present study was performed to evaluate the adverse effects of KR-30035, a multidrug-resistance modulator, on the cardiovascular system in vivo, along with its effect on paclitaxel-induced cell cycle arrest in cultured cancer cells. In anesthetized rats, KR-30035 was about 10-fold less potent than verapamil in lowering blood pressure (i.v. ED20 0.320+/-0.052 and 0.034+/-0.005 mg/kg, respectively) and in producing electrocardiogram changes. In conscious spontaneously hypertensive rats, verapamil caused a significant antihypertensive effects at the doses tested (p.o. ED20, 7.8+/-4.0 mg/kg), whereas KR-30035 did not significantly change either the blood pressure or the heart rate at any doses tested (up to 100 mg/kg). The estimated i.v. LD50 values in mice were 5.9 and 48.9 mg/kg for verapamil and KR-30035, respectively. In the presence of 10 microM KR-30035, paclitaxel (1 microM) when added to cultures of HCT15/CL02 human cancer cells greatly shifted the cell population from the G0/G1 phases towards G2/M phases (from 42.4, 30.3 and 27.3 to 14.6, 21.5 and 63.9% for the G0/G1, S and G2/M phases, respectively), with a similar magnitude to that of 10 microM verapamil (14.0, 15.7 and 70.3%, respectively). These results suggest that KR-30035 has weaker in vivo effects on the cardiovascular system compared with verapamil, while potentiating the G2/M arresting effect of paclitaxel on the cell cycle.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tetra-Hidronaftalenos
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Verapamil
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Sistema Cardiovascular
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Ciclo Celular
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Anti-Hipertensivos
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2000
Tipo de documento:
Article