Enhancement by dexamethasone of the therapeutic benefits of cisplatin via regulation of tumor angiogenesis and cell cycle kinetics in a murine tumor paradigm.
We have investigated in the current study, the possible modulatory effects of dexamethasone on cisplatin cytotoxicity in Ehrlich ascites carcinoma (EAC)-bearing female Swiss albino mice. Cisplatin (3.5mg/kg) was injected IP for 3 consecutive days in mice previously inoculated SC with EAC cells in the right flank. Dexamethasone (2.5mg/kg) was administered SC alone or 24h ahead of cisplatin challenge, and these regimens were given for 3 consecutive days. Dexamethasone enhanced the anti-tumor effects of cisplatin, clearly demonstrated by the increased mean tumor growth time (TGT) and tumor growth delay time (TGDT) values compared to cisplatin alone. The effects of dexamethasone on tumor angiogenesis and cell cycle distribution of EAC cells have been addressed as possible mechanisms, whereby the glucocorticoid could probably augment cisplatin cell-kill. Indeed, dexamethasone enhanced the angiostatic activity of cisplatin by 52.5%. The glucocorticoid also synchronized the EAC cells in the G2/M phase, secondary to its regulatory role on the transcriptional and translational activity in these cells, thus, exposing them to the dramatic cytotoxic potential of cisplatin. One could conclude that dexamethasone enhanced the anti-tumor effects of cisplatin via augmenting its angiostatic activity and modulating cell cycle kinetics. Also, dexamethasone did not alter cisplatin-induced nephrotoxicity, thus demonstrating an improved therapeutic potential.
Dept. of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Egypt. hmmarafa@yahoo.com
Hossam M M
HM
Arafa
Mostafa A
MA
Abdel-Hamid
Abeer A K
AA
El-Khouly
Mohamed M A
MM
Elmazar
Abdel-Moneim M
AM
Osman
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols; D001806:Blood Urea Nitrogen; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D003404:Creatinine / Q000097:blood; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D008315:Malondialdehyde; D003907:Dexamethasone; D003404:Creatinine; D005978:Glutathione; D002945:Cisplatin