Sequence-dependent enhancement of HCT-8 cell kill by trimetrexate and fluoropyrimidines: Implications for the mechanism of this interaction

Phase II trial of trimetrexate for patients with advanced gastric carcinoma

“…The sequence of 5‐FU and TMTX administration appears to be important, because synergistic cytotoxicity was seen when TMTX was added before 5‐FU. When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25.…”

“…When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25. In cell lines, 5‐FU and leucovorin showed increased cytotoxicity in the presence of TMTX, which was greater than the combination of 5‐FU and TMTX alone 26.…”

Phase II trial of trimetrexate for patients with advanced gastric carcinoma

“…The sequence of 5‐FU and TMTX administration appears to be important, because synergistic cytotoxicity was seen when TMTX was added before 5‐FU. When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25.…”

“…When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25. In cell lines, 5‐FU and leucovorin showed increased cytotoxicity in the presence of TMTX, which was greater than the combination of 5‐FU and TMTX alone 26.…”

A Phase I/II Study of Trimetrexate and Capecitabine in Patients With Advanced Refractory Colorectal Cancer

“…In vitro data shows that adding TMTX to 5-FU/LV clearly enhances cytotoxicity against colon cancer cells. 12 Based on encouraging preclinical data, 2 phase II studies of TMTX, 5-FU, and LV in previously untreated patients with advanced CRC were conducted and demonstrated overall response rates of 50% and 36%, respectively. 14,15 Capecitabine is an oral fluoropyrimidine that is absorbed intact from the gastrointestinal tract and converted to 5-FU.…”

“…TMTX does not use the reduced folate transport system to enter neoplastic cells, thus avoiding competition for uptake when administered with LV, thereby making it a particularly useful adjunct to 5-FU. 12,13 TMTX possesses activity against CRC in both preclinical and clinical studies. In vitro data shows that adding TMTX to 5-FU/LV clearly enhances cytotoxicity against colon cancer cells.…”

The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

“…"~ Phosphono-N-acetyl-L-aspartic acid and pyrazofurin both increase FU-RNA by depleting uridine triphosphate stores. Use of this combination has been restricted greatly by its prohibitive neurotoxicity.13' Hydroxyurea, polyriboinosinic-polyribocytidylic acid, methotrexate, and hypoxanthine also have been studied, but their action is complex and poorly predictab]e. 40,[131][132][133]…”

Phase II trial of trimetrexate for patients with advanced gastric carcinoma

“…The sequence of 5‐FU and TMTX administration appears to be important, because synergistic cytotoxicity was seen when TMTX was added before 5‐FU. When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25.…”

“…When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25. In cell lines, 5‐FU and leucovorin showed increased cytotoxicity in the presence of TMTX, which was greater than the combination of 5‐FU and TMTX alone 26.…”

A Phase I/II Study of Trimetrexate and Capecitabine in Patients With Advanced Refractory Colorectal Cancer

“…In vitro data shows that adding TMTX to 5-FU/LV clearly enhances cytotoxicity against colon cancer cells. 12 Based on encouraging preclinical data, 2 phase II studies of TMTX, 5-FU, and LV in previously untreated patients with advanced CRC were conducted and demonstrated overall response rates of 50% and 36%, respectively. 14,15 Capecitabine is an oral fluoropyrimidine that is absorbed intact from the gastrointestinal tract and converted to 5-FU.…”

“…TMTX does not use the reduced folate transport system to enter neoplastic cells, thus avoiding competition for uptake when administered with LV, thereby making it a particularly useful adjunct to 5-FU. 12,13 TMTX possesses activity against CRC in both preclinical and clinical studies. In vitro data shows that adding TMTX to 5-FU/LV clearly enhances cytotoxicity against colon cancer cells.…”

The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

“…"~ Phosphono-N-acetyl-L-aspartic acid and pyrazofurin both increase FU-RNA by depleting uridine triphosphate stores. Use of this combination has been restricted greatly by its prohibitive neurotoxicity.13' Hydroxyurea, polyriboinosinic-polyribocytidylic acid, methotrexate, and hypoxanthine also have been studied, but their action is complex and poorly predictab]e. 40,[131][132][133]…”

Phase II trial of trimetrexate for patients with advanced gastric carcinoma

“…The sequence of 5‐FU and TMTX administration appears to be important, because synergistic cytotoxicity was seen when TMTX was added before 5‐FU. When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25.…”

“…When the sequence was reversed and 5‐FU was given before TMTX, antagonism was observed 25. The mechanism of synergy is thought to be due to increased intracellular accumulation of 5‐phosphoribosyl‐1‐pyroposphate caused by antifolate inhibition of purine synthesis 25. In cell lines, 5‐FU and leucovorin showed increased cytotoxicity in the presence of TMTX, which was greater than the combination of 5‐FU and TMTX alone 26.…”

A Phase I/II Study of Trimetrexate and Capecitabine in Patients With Advanced Refractory Colorectal Cancer

“…In vitro data shows that adding TMTX to 5-FU/LV clearly enhances cytotoxicity against colon cancer cells. 12 Based on encouraging preclinical data, 2 phase II studies of TMTX, 5-FU, and LV in previously untreated patients with advanced CRC were conducted and demonstrated overall response rates of 50% and 36%, respectively. 14,15 Capecitabine is an oral fluoropyrimidine that is absorbed intact from the gastrointestinal tract and converted to 5-FU.…”

“…TMTX does not use the reduced folate transport system to enter neoplastic cells, thus avoiding competition for uptake when administered with LV, thereby making it a particularly useful adjunct to 5-FU. 12,13 TMTX possesses activity against CRC in both preclinical and clinical studies. In vitro data shows that adding TMTX to 5-FU/LV clearly enhances cytotoxicity against colon cancer cells.…”

The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

“…"~ Phosphono-N-acetyl-L-aspartic acid and pyrazofurin both increase FU-RNA by depleting uridine triphosphate stores. Use of this combination has been restricted greatly by its prohibitive neurotoxicity.13' Hydroxyurea, polyriboinosinic-polyribocytidylic acid, methotrexate, and hypoxanthine also have been studied, but their action is complex and poorly predictab]e. 40,[131][132][133]…”