Flavone Acetic Acid (FAA) is a new agent that was discovered by the Drug Evaluation Branch (DEB) of NCI is currently in Phase I clinical trials. In preclinical studies, FAA was found to be curative for colon #38 and (surprisingly) was found to be essentially devoid of activity against the primary screen, P388 leukemia. DEB later established that FAA was also active against B16 melanoma, a human amelanotic melanoma, and modesty active against L1210 leukemia. Added to these results, we have found that FAA is broadly active in mice against a variety of solid tumors (Colon #51, #07, #10, #26; Pancreatic Adenoca. #02 and #03; Mammary Adenoca. #16/C/Adr, Glascow Osteosarcoma, and the M5076 ovarian tumor). Thus, for the first time an agent has been identified with very broad solid tumor activity (specifically). The main drawback of FAA is an unusual """"""""threshold"""""""" behavior in which a narrow range of dosages are active (a narrow window of efficacy) and splitting the dose markedly decreases activity. Proposed studies will include: 1) Analogue Development: Evaluation in-vitro and in-vivo of selected analogues very close in structure to FAA, as well as a broad range of flavone-like analogues in order to define the structure-activity relationship and attempt to isolate analogues with greater therapeutic activity and a broader window of efficacy. We have seen that considerable structural changes can take place with retention of curative activity. 2) Mechanism of Action: Biochemical and cellular studies will be correlated in-vitro and in-vivo. Biochemical: i) intracellular distribution of labeled FAA, ii) binding of FAA to DNA (formation and repair, kinetics of both), iii) single-strand breaks and cross-links following FAA exposure (assayed by alkaline elution). Cellular: i) define the kinetics of cell killing, ii) examine proliferation dependence of cytotoxicity, iii) determine the phase(s) of the cell cycle in cell killing, iv) and examine cross-resistance patterns. 3) Pharmacokinetic Studies: The change in FAA concentration in the urine with changing dosages will be evaluated to determine nonlinear renal tubular secretion (as occurs for many other organic acids; e.g., salicylates, and many penicillins). Probenecid will be evaluated with FAA to decrease the threshold by decreasing tubular secretion (thus increasing the window of efficacy). The proportionally of peak levels and AUC's with changing doses of FAA and selected analogs will also be determined within a sensitive tumor to further evaluate the nonlinearity of the pharmacokinetics and antitumor efficacy.
