Cytotoxic Action of Novel Antineoplastic Agents
In collaboration with research scientists at Mayo and elsewhere, along with members of the Phase I and Phase II clinical trials programs in the Developmental Therapeutics Program of the Mayo Clinic Cancer Center, the Kaufmann laboratory studies the action of promising investigational anticancer drugs in preclinical models and/or in the clinical setting. Agents that have previously been investigated in the Kaufmann laboratory include pyrazoloacridine, a dual topoisomerase I/topoisomerase II inhibitor that diminishes repair of platinum-DNA adducts; 6-aminonicotinamide, a niacin antagonist that enhances cisplatin accumulation and cytotoxicity in a wide variety of cancer cells; CI-1033, a tyrosine kinase inhibitor that modulates the uptake of camptothecin analogues in ABG2-expressing cancer cells; and adaphostin, a tyrphostin that generates reactive oxygen species by inhibiting mitochondrial electron transport.
One major effort in the laboratory is focused on understanding mechanisms of resistance to farnesyltransferase (FT) inhibitors (FTIs). These agents have shown promising activity against acute myelogenous leukemia in elderly patients. Our recent studies of leukemic cells from patients enrolled in a phase II trial of the FTI tipifarnib have demonstrated that leukemia cells exhibit one of three responses to tipifarnib: i) no inhibition of FT, ii) inhibition of FT but no response, or iii) inhibition of FT and a clinical response. Efforts are currently under way to determine the basis for the first two of these phenotypes.
Other efforts are focused on inhibitors of the ATR/Chk1 and PI3 kinase/Akt/mTOR pathways as potential modulators of drug sensitivity.