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

Sobrero, Alberto; Romanini, Antonella; Russello, Orsolina; Nicolin, A; Rosso, Riccardo; Bertino, Joseph R.

doi:10.1016/0277-5379(89)90157-0

Cited by 14 publications

(6 citation statements)

References 9 publications

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“…"~ 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]…”

Section: Modulation Of Pyrimidine Metabolismmentioning

confidence: 99%

The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

Robben

Pippas

Moore

1993

Cancer

166

105

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Background. A case of reversible cardiogenic shock linked to 5‐fluorouracil (5‐FU) was observed. Recognizing the increasing use of 5‐FU, the authors tried to map this syndrome. Methods. They reviewed 134 additional case reports, retrieved information from literature searches, focused on clinical features, and discussed possible pathophysiologic findings and prevention of this syndrome. Results. Although angina and electrocardiographic changes were common and reproducible (approximately 90% each), coronary artery disease was found in a few patients. A total of 33 patients had severe left ventricular dysfunction, 28 without evidence of myocardial infarction. The symptoms were responsive to conservative management (90%). Conclusions. Cardiac toxicity is a little known complication of 5‐FU therapy, with an unknown but significant incidence. It is highly treatable.

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Section: Modulation Of Pyrimidine Metabolismmentioning

confidence: 99%

The syndrome of 5-fluorouracil cardiotoxicity. An elusive cardiopathy

Robben

Pippas

Moore

1993

Cancer

166

105

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Phase II trial of trimetrexate for patients with advanced gastric carcinoma

Ramanathan

Lipsitz

Asbury³

et al. 1999

Cancer

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BACKGROUND A Phase II study was conducted to evaluate the response, duration of response, and duration of survival of patients with measurable gastric carcinoma treated with trimetrexate (TMTX) who had not had prior chemotherapy. METHODS Thirty‐three patients with unresectable or metastatic gastric adenocarcinoma who had not received previous chemotherapy were treated with intravenous TMTX 12 mg/m2 daily for 5 days. The dosage of TMTX was reduced to 8 mg/m2 daily for 5 days for those who had received prior radiotherapy. The cycle was repeated every 3 weeks until disease progression or unacceptable toxicity occurred. RESULTS Thirty‐three patients could be analyzed with follow‐up data. There was one Grade 5 (lethal) toxicity and four Grade 4 toxicities. Hematologic toxicity was the most common. The overall response rate was 21%, the overall median progression free survival was 2.7 months, and the overall median survival was 5.9 months for the entire cohort. No patients were alive at last follow‐up. CONCLUSIONS Though TMTX as a single agent has activity in gastric carcinoma with manageable toxicity, it cannot be recommended for routine use as a single agent due to the brief duration of response and median survival. Cancer 1999;86:572–6. © 1999 American Cancer Society.

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“…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.…”

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confidence: 99%

“…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.…”

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confidence: 99%