Extensive pre-clinical studies have demonstrated that depletion of tumor ATP by greater than 85% can enhance tumor response to standard cytotoxic anti-neoplastic agents. This enhanced response is obtained with significantly lower doses of the anti-neoplastic agent. The proposed ATP and pyrimidine depleting regimen consists of 3 drugs, 6-methylmercaptopurine riboside (MMPR), 6-aminonicotinamide (6AN), and N-(phosphonacetyl)-L-aspartate (PALA). While MMPR and PALA have been combined clinically, the optimal biologically active dose of 6AN in combination with PALA and MMPR has not been determined. 6AN is known to inhibit glycolysis and pentose phosphate pathway which is manifested biochemically by a decrease in ATP and an increase in 6-phosphogluconate (6PG) in the tumor. In this application, we propose to use clinical 31P nuclear magnetic resonance (NMR) spectroscopy to monitor tumor metabolism after administration of 6AN to detect the biologically active dose of 6AN and evaluate clinical toxicity. Specifically, we will use 1H decoupled 31P NMR spectroscopy to detect 6PG and changes in NTP (nucleoside triphosphates) in response to 6AN (and PALA, MMPR) at clinically relevant doses. Changes in NTP and detection of 6PG will determine the biologically active dose of 6AN. We will a)determine quantitatively the effect of 6AN dose escalation on changes in NTP and SPG, b) determine the optimal dose of 6-AN (with a fixed dose of MMPR and PALA) as an NTP depleting strategy in combination with paclitaxel, c) after defining the optimal dose of 6-AN, determine the maximum tolerated dose (MTD) of paclitaxel in combination with MMPR, PALA, and 6-AN. We will determine if measurements of 6PG in peripheral blood mononuclear cells are a surrogate for measurement of tumor measurements of 6PG and predicts activity of 6AN in tumors. We will also determine the relationship between quantitative measurements of NTP, 6PG and tumor response. It is hypothesized that decreases in NTP > 50% and the presence of 6PG with a peak area comparable (>50%) to other detected metabolites (such as phosphocholine (PC) or phosphoethanolamine (PE)) will be necessary to induce responses. The doses determined in these studies, will allow further Phase II studies of this strategy. If measurements of 6PG in peripheral blood lymphocytes correlate with tumor 6PG, future studies would not require further NMR studies. ? ?
