Lonidamine as a modulator of alkylating agent activity in vitro and in vivo.

摘要: We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by agents if defenses requiring. Exposure cells to lonidamine (500 microM) 2 h under hypoxic conditions followed 1-h exposures plus normally oxygenated in vitro significantly increased cell kill achieved cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold D-tetraplatin 10-fold at 90% inhibitory concentration MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In MCF-7 parent line, treatment with CDDP cytotoxicity 10-fold, carboplatin 8-fold concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), N,N'-bis(2-chloroethyl)-N-nitrosourea, resistance evident lines compared line. Treatment each drug 1.5- 3-fold both lines. When exposure extended 24 before 12 after cultures, (250 100-fold, but melphalan only 2- over range tested. FSaIIC murine fibrosarcoma tumor system, five i.p. injections 50 mg/kg 36 dose tested when platinum complexes were given immediately third injection. cyclophosphamide thiotepa same schedule, increases killing on excision assay dosage ranges. The bone marrow toxicity caused addition less than Finally, EMT6 mammary carcinoma, use 500 twice daily along CDDP, carboplatin, thiotepa, growth delays 1.6- 3.0-fold. results suggest agent may be a clinically useful adjunctive therapy these drugs.