Enantioselectivity of thalidomide serum and tissue concentrations in a rat glioma model and effects of combination treatment with cisplatin and BCNU.
Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.
Murphy
Susan
S
Bill Walsh Cancer Research Laboratories, Department of Medical Oncology, University of Sydney at Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
Boyle
Frances M
FM
Davey
Ross A
RA
Gu
Xiao-Qing
XQ
Mather
Laurence E
LE
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols; D002330:Carmustine / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013792:Thalidomide / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D013792:Thalidomide; D002945:Cisplatin; D002330:Carmustine