Mutagenicity of some topoisomerase II-interactive agents

Among the anticancer drugs currently used in the treatment of human malignancies, as well as several new series of drugs under development, are targeted at topoisomerase II enzymes. Besides of inducing cell death due to both 'mitotic catastrophe' and the induction of apoptosis, topoisomerase-II-targeted drugs can increase the frequency of cells bearing mutations. These cells can develop resistance to the therapeutic agents or may lead to the development of secondary tumours and abnormal reproductive outcomes. This review focuses on the mutagenic properties of the topoisomerase II poisons etoposide, doxorubicin and amsacrine, which are front-line therapies for a variety of malignancies, and genistein, which is prominent in soybean foods and is believed to be a chemopreventative agent that contributes to the low incidence of specific cancers among Asian populations. In addition, the topoisomerase II catalytic inhibitor merbarone that is in clinical trials as an anticancer agent will be discussed. It clear from the present review that, the topoisomerase II-interactive anticancer agents appear to be mutagenic. Therefore, the clinical use of these mutagenic drugs must be weighed against the risks of secondary malignancies in cured patients and persistent genetic damage of their potential offspring

effects of oral grape seed extract on cisplatin-induced cytogenotoxicity in mice

The present investigation was directed to study the possible chemoprotective activity of orally administered grape seed extract [GSE] against cisplatin-induced cytotoxicity and genotoxicity towards mouse somatic and germinal cells in vivo. Pretreatment of mice with GSE [100 mg/kg/day] for 7 days and simultaneously with a single dose of cisplatin [2.2 or 5.5 mg/kg, i.p.] for another day, significantly reduced the frequency of bone marrow micronucleated polychromatic erythrocytes by factors of 1.9 and 1.28, respectively. Furthermore, GSE caused a reduction in bone marrow suppression induced by cisplatin treatment, particularly before the lower dose. In male germline, orally administration of GSE [100 mg/kg/day] for 7 consecutive days before and 7 consecutive days after treatment with a single dose of cisplatin [2.2 or 5.5 mg/kg, i.p.], significantly elevated the levels of sperm motility reduced by cisplatin treatment. Furthermore, GSE significantly decreased the elevated levels of sperm head abnormality induced with cisplatine by factors of 1.6 and 1.2, respectively. Our results indicate that GSE plays a role in attenuating the genotoxicity induced by cisplatin and may provide decreases in the development of secondary malignancy and abnormal reproductive outcomes risks

Protective effect of captopril against cisplatin induced nephrotoxicity in rats

This study has been initiated to determine whether captopril, an angiotensin-converting enzyme [ACE] inhibitor containing sulfhydryl [-SH] group can protect against cisplatin-induced nephrotoxicity in rats. A single dose of cisplatin [7.5mg/kg bwt] injected i.p. caused a significant increase in blood urea nitrogen [BUN] and creatinine levels amounting to 402% and 573%, respectively with a marked elevation in lipid peroxides measured as malondialdehyde [MDA] content [54%], accompanied by a significant decrease in reduced glutathione [GSH] content [27%] of kidney tissue as compared to control group. In addition, there were marked increases in kidney tissue content of nitric oxide [NO] [43%] and plasma endothelin-1[ET-1] [37%]. On the other hand, administration of captopril [60mg/kg bwt, i.p.] 1 h before cisplatin protected the kidney as indicated by restoration of BUN, creatinine, MDA, GSH, NO and ET-1. These results indicate that captopril, an ACEI, has a protective effect against cisplatin-induced damage to kidney. This reflects the beneficial role of captopril in treatment of renovascular hypertention and congestive heart failure; an effect that may be related to its free radicals scavenging and antioxidant effects which are sulfhydryl dependent