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.