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Journal of Biological Sciences

Year: 2003 | Volume: 3 | Issue: 11 | Page No.: 961-972
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Research Article

Genotoxicity and Cytotoxicity of the Anticancer Drugs Gemcitabine and Cisplatin, Separately and in Combination: in vivo Studies

Magdy S. Aly, Mohamad B. Ashour, Soheir M. El Nahas and Mona A. F. Abo Zeid

ABSTRACT

Both gemcitabine (2`,2`-difluorodeoxycytidine, dFdC) and cisplatin (cis-diammine-dichloroplatinum) have significant anticancer activity against ovarian, head and neck and non-small cell lung cancer (NSCLC). dFdC can be incorporated into DNA and RNA and inhibit DNA repair, while cisplatin can form Pt-DNA abducts. Because of differences in mechanisms of action and toxicity profiles, combination of the two drugs has enormous clinical potential. The combination of both is increasingly applied in clinical oncology. In this study, the genotoxic effects of cisplatin and gemcitabine separately and in combination were detected in the male mice bone marrow cells. Four doses were used for each drug. In CDDP experiments 6, 12, 24 and 36 mg kg‾1 body weight were used. For dFdC 40, 50, 60 and 80 mg kg‾1 body weight were used. Three drug combination doses were used: 4 mg kg‾1 body wt. CDDP, 20 mg kg‾1 body wt. dFdC; 6 mg kg‾1 body wt. CDDP, 20 mg kg‾1 body wt. dFdC; and 8 mg kg‾1 body wt. CDDP, 20 mg kg‾1 body wt. dfdC. In the drug combination experiments, CDDP were injected 4 hours prior to dfdC. Total chromosomal aberrations and sister chromatid exchanges (SCEs) frequencies were increased after exposure to combined drugs compared to exposure to each drug separately. Both single and combined drugs decreased the mitotic activity of the cells and induced a cell cycle delay with increasing the doses. In conclusion, the potentiation in chromosomal aberrations and sister chromatid exchanges formation might be a result of the inhibition of DNA repair by dFdC. The synergism between dFdC and CDDP appears to be mainly due to an increase in Pt-DNA adduct formation possibly related to changes in DNA due to dFdC incorporation into DNA.
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