Although 5-FU is the most effective drug for the treatment of colorectal carcinoma, response rates (10-20%) are quite low; therefore, colon tumors are either initially or subsequently resistant to this agent. 5-FU resistance in vitro has been linked to high intracellular levels of uridine nucleotides (DUMP and UTP), which compete with 5-FU metabolites for target site (TMP synthase, RNA), and to rapid elimination of FdUMP via dephosphorylation and transmembrane efflux. An additional mechanism of resistance to 5-FU is enhanced utilization of preformed uridine (Urd) by tumor cells via the pyrimidine salvage pathway. The goal of the proposed clinical and laboratory studies is to increase response rates to FU therapy by overcoming these resistance mechanisms with PALA (blocks de novo pyrimidine synthesis), and thus lowers intracellular pools of competing nucleotides, DUMP and UTP, and dipyridamole (DP) which blocks nucleoside transport and thus blocks the pyrimidine salvage pathway. DP may further enhance 5-FU action by preventing cellular efflux of FU- nucleosides (DFURD FdUrd) and thus allow them to be re-anabolized to athe active metabolites FUTP and FdUMP. The first area of technology transfer from prior laboratory observations to practical clinical application will involve the use of PALA to lower tumor cell UTP and DUMP levels. Initial Phase I trials will determine the lowest dose of PALA which has a near-maximum quantifiable biochemical effect, i.e., lowers plasma Urd and inhibits WBC ATCase activity for at least 6 days. A concurrent Phase I trial with PALA + DP will discern the ability of DP to enhance PALA's effects by blocking salvage from plasma nucleosides, Dthd and Urd. Having determined the """"""""optimal low dose of PALA"""""""" for effective biochemical modulation, the MTD of 5-FU will then be determined. These concurrent Phase I studies will be followed by a randomized (2 concurrent) Phase II trials of PALA/5-FU vs. DP/PALA/5-FU in untreated patients with advanced colorectal carcinoma. The expected response range (CR+PR) for each arm is at least 30-40%. Fresh surgical specimens from selected patients will be examined to determine intrinsic pools of DUMP & UTP and assess TMP synthase activity to discern the range of these parameters in human tumors before therapy. Additional biopsies will be obtained after 5-FU administration at the nadir of plasma Urd following PALA + DP treatment. This will determine the range of attained FdUMP pools, the accumulation of DUMP, and the inhibition of TMP synthase as a function of the DUMP/FdUMP ratio. These cellular studies will be useful in integrating the results of the clinical trial and will establish a data base for use in the design of future clinical investigative approaches. Re-biopsy of tumor specimens in responding patients at athe time of disease exacerbation will elucidate possible biochemical mechanisms of drug resistance. The optimal dosages and schedule as determined by the Phase I laboratory and clinical observations will be tested in a Phase II protocol in untreated patients with advanced colorectal cancer. Continued laboratory monitoring will continue throughout this Phase II trial. These results and experience in the use of these techniques with clinical samples will have applicability to other 5-FU-sensitive human neoplasms such as breast, head and neck and ovarian cancer.
| Fleming, R A; Capizzi, R L; Muss, H B et al. (1996) Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer. Clin Cancer Res 2:1107-14 |
