Modulation of alkylating agents by lonidamine in vivo

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 alkylating agents if cellular defenses are energy-requiring. In the FSaIIC murine fibrosarcoma tumor system, 5 intraperitoneal (IP) injections of 50 mg/kg of lonidamine over 36 hours increased the tumor cell kill by cisplatin, carboplatin, D-tetraplatin, melphalan and BCNU approximately two- to threefold over the dosage ranges of each drug tested when the antitumor agents were given IP immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges for each drug. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents, cisplatin, carboplatin, and BCNU was less than for tumor cells. Dose modifying effects were observed in the killing of bone marrow colony forming units-granulocyte-macrophage progenitors (CFU-GM) by cyclophosphamide, thiotepa and melphalan but at standard doses of cyclophosphamide and thiotepa there was no increase in the killing of bone marrow CFU-GM with the addition of lonidamine to treatment with these drugs. The results suggest that lonidamine can positively modulate tumor cell killing by some antitumor alkylating agents and may be a clinically useful adjunctive therapy with these drugs.