Efficacy of a mitochondrial toxin, F16, in a multi-ATP-depleting regimen + chemotherapy on human breast cancer (MDA-MB-468) xenografts

2096 Background: : Chemotherapy is enhanced by multi-ATP-depleting therapy (Cancer Res. 60: 6776, 2000). Malignant tumors generally increase ATP production to increase cell division. In general, tumors make and consume (deplete) more ATP than normal tissues. If ATP production is equally inhibited in normal and tumor tissues, high ATP consumption (depletion) in tumors should deplete ATP to cytocidal levels, whereas the lower ATP consumption in normal cells should reduce ATP to tolerable levels. This rationale requires multiple ATP inhibitors inhibiting multiple biochemical pathways that produce ATP. Methods: Alanosine (AL), inhibitor of AMP synthesis, + 6-methylmercaptopurine riboside (MMPR), inhibitor of purine synthesis, preceded by PALA, a pyrimidine inhibitor; acronym, PALM. F16 blocks ATP synthesis by selectively accumulating in mitochondria of responsive breast cancers (Cancer Cell 2:29, 2002). Results: F16 alone was not effective. Taxotere alone (TXT), at MTD40, affects 100% PR of tumors. The addition of PALM (P100 AL250 M150), or PALM + F16 10, effects the same 100% P.R. at half the TXT dose (TXT20), suggesting clinical benefit at reduced normal tissue toxicities. Follow-up (120 days) demonstrates substantial tumor recurrence (43–50%) in Groups 1 and 2, and minimal recurrence (17%) in Group 3. Conclusions: A multi-ATP-depleting regimen (PALM + F16) + chemotherapy augments tumoricidal capability. Chemotherapy is at markedly lower doses, strongly suggesting lower toxic side-effects in the clinic. No significant financial relationships to disclose.