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Drugs Apr 1995Trimetrexate is a folinic acid analogue structurally related to methotrexate, whose primary mechanism of action is believed to be inhibition of dihydrofolate reductase.... (Review)
Review
Trimetrexate is a folinic acid analogue structurally related to methotrexate, whose primary mechanism of action is believed to be inhibition of dihydrofolate reductase. This reduces the production of DNA and RNA precursors and leads to cell death. Trimetrexate is lipophilic and can passively diffuse across cell membranes including those of Pneumocystis carinii and its mammalian host. To minimise toxicity, trimetrexate must be coadministered with calcium folinate (leucovorin calcium), a reduced folate coenzyme, which is transported into, and protects, mammalian host cells but not P. carinii cells. In noncomparative trials trimetrexate was effective in the treatment of P. carinii pneumonia (PCP) in patients with AIDS who were intolerant of or refractory to cotrimoxazole (trimethoprim/sulfamethoxazole) and pentamidine treatment. In these patients, 2- to 4-week survival rates of 48 to 69% were reported. In a comparative trial in the initial therapy of PCP, trimetrexate was less effective than cotrimoxazole in moderate to severe disease as evidenced by a significantly higher failure rate. Trimetrexate was better tolerated than cotrimoxazole when used in this setting, however. Significantly fewer patients receiving trimetrexate plus calcium folinate discontinued treatment because of adverse events than did patients receiving cotrimoxazole. The most common adverse effect associated with trimetrexate is myelosuppression (neutropenia and thrombocytopenia); this is mitigated by coadministration of calcium folinate and is generally reversible upon dosage reduction or discontinuation. Other adverse effects include increases in serum aminotransferase levels, anaemia, fever, rash/pruritus, and increased alkaline phosphatase or serum creatinine levels. Further research into the use of trimetrexate, including its efficacy as prophylaxis, in combination with other agents and as an oral formulation, is needed to clearly define its role in the treatment of PCP and to identify patients most likely to benefit. Currently, trimetrexate should be considered as an alternative treatment option in immunocompromised patients with moderate to severe PCP who have not responded to or are intolerant of first-line therapy.
Topics: AIDS-Related Opportunistic Infections; Animals; Clinical Trials as Topic; Humans; Pneumonia, Pneumocystis; Rats; Trimetrexate
PubMed: 7789290
DOI: 10.2165/00003495-199549040-00007 -
Journal of Clinical Oncology : Official... Dec 1987Trimetrexate is a promising new lipophilic antifolate with antitumor and antimicrobial activity, which is currently undergoing clinical trials. It differs from... (Clinical Trial)
Clinical Trial Review
Trimetrexate is a promising new lipophilic antifolate with antitumor and antimicrobial activity, which is currently undergoing clinical trials. It differs from methotrexate in its transport and intracellular retention, and may be useful against tumors resistant to methotrexate because of impaired transport or deficient polyglutamylation. In preclinical studies, it has demonstrated a broader spectrum of antitumor activity than methotrexate, and appears to have synergistic antitumor activity when combined with a number of other agents. In clinical trials, the primary toxicity has been hematologic, with rapid recovery and no evidence of cumulative dose effect. Nonhematologic toxicity has been sporadic. Preliminary results of phase II trials indicate activity against breast, non-small-cell lung, and head and neck tumors. In addition, trimetrexate with simultaneous leucovorin rescue appears to be a promising new treatment for pneumocystis pneumonia in AIDS patients, with minimal toxic side effects.
Topics: Animals; Antineoplastic Agents; Clinical Trials as Topic; Humans; Neoplasms; Quinazolines; Trimetrexate
PubMed: 2960788
DOI: 10.1200/JCO.1987.5.12.2032 -
Journal of the National Cancer Institute Oct 1988
Topics: Antineoplastic Agents; Folic Acid Antagonists; Humans; Quinazolines; Trimetrexate
PubMed: 2971816
DOI: 10.1093/jnci/80.16.1268 -
Clinical Pharmacokinetics Mar 1994Trimetrexate represents one of a number of new antimetabolites that have been studied in malignant, rheumatological and infectious disease. Methotrexate, the classical... (Review)
Review
Trimetrexate represents one of a number of new antimetabolites that have been studied in malignant, rheumatological and infectious disease. Methotrexate, the classical antifolate agent, is active in a broad spectrum of clinical settings, but its use is limited ny pre-existing or acquired cellular resistance. Trimetrexate is an agent that does not require uptake by the folate carrier transport system, a major mechanism of cellular resistance both in vitro and in vivo. Both dihydrofolate reductase inhibition and high performance liquid chromatography (HPLC) assays can be used to determine drug concentrations. Clearance of trimetrexate has been reported to follow biphasic or triphasic patterns. Elimination is primarily by biotransformation with less than 5% of the drug excreted renally in an unchanged form. Both active and inactive metabolites have been found, but the precise metabolic pathways have yet to be defined. The role of trimetrexate in the treatment of Pneumocystis carinii pneumonia is limited to compassionate use, as clinical studies have shown cotrimoxazole (trimethoprim-sulfamethoxazole) to be superior to trimetrexate. However, in a wide spectrum of malignant processes, trimetrexate appears to have a role either as a high-dose single agent, with calcium folinate (leucovorin calcium) rescue, or in combination with other antineoplastic agents. However, further trials are needed to fully establish the efficacy of trimetrexate in these settings. Increased knowledge of the pattern of resistance for individual tumours and tumour types may result in trimetrexate becoming more widely used clinically.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Immunocompromised Host; Multicenter Studies as Topic; Neoplasms; Pneumocystis Infections; Tissue Distribution; Toxoplasmosis; Trimetrexate
PubMed: 8194282
DOI: 10.2165/00003088-199426030-00003 -
Seminars in Oncology Oct 1997Unresectable metastatic colorectal cancer remains a significant cause of morbidity and mortality in both the United States and Europe. To date, no chemotherapeutic... (Review)
Review
Unresectable metastatic colorectal cancer remains a significant cause of morbidity and mortality in both the United States and Europe. To date, no chemotherapeutic regimen for this disease has demonstrated a definitive survival advantage compared with 5-fluorouracil (5-FU) plus leucovorin (LV). However, recent trials have raised the possibility that the combination of trimetrexate (TMTX) plus 5-FU/LV may improve response rates and survival in patients with metastatic colorectal cancer. Trimetrexate is a nonclassical antifolate that has demonstrated antitumor activity against a number of malignancies, including those resistant to the classical antifolate methotrexate. While the single-agent activity of TMTX remains modest in metastatic colorectal cancer, the combination of TMTX/5-FU/LV has shown significant activity in several phase II trials. Reported studies include a phase II trial in chemotherapy failures that demonstrated a 20% response rate, and two multicenter phase II trials in previously untreated patients that demonstrated 50% and 38% overall response rates, respectively. Diarrhea was the dose-limiting toxicity in all trials, although a regimen of scheduled loperamide was quite effective in mitigating this complication. These studies are being followed up with two confirmatory phase II studies in chemorefractory patients and two randomized phase III trials comparing TMTX/5-FU/LV with standard 5-FU/LV.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Folic Acid Antagonists; Humans; Trimetrexate
PubMed: 9420022
DOI: No ID Found -
Seminars in Oncology Oct 1997Trimetrexate (TMTX), a potent inhibitor of the enzyme dihydrofolate reductase, is biochemically and metabolically similar to methotrexate (MTX). Fundamental differences... (Review)
Review
Trimetrexate (TMTX), a potent inhibitor of the enzyme dihydrofolate reductase, is biochemically and metabolically similar to methotrexate (MTX). Fundamental differences between TMTX and MTX, however, mandate investigation of TMTX in both MTX-sensitive and MTX-resistant tumors. In a number of phase II clinical trials, the antitumor activity of single-agent TMTX has been variable, in part because of the heterogeneity of doses and schedules used and in part because of diverse patient populations. Single-agent activity has been documented in some commonly occurring tumors, including breast, non-small cell lung, and head and neck cancers. Other tumors with sensitivity to single-agent TMTX include transitional cell carcinomas of the urothelium, prostate cancer, and gastric carcinoma. In a small series of children with renal cell carcinoma, significant clinical activity was suggested. The single-agent activity of TMTX, coupled with the finding that TMTX may act as a biochemical modulator of 5-fluorouracil/leucovorin, suggests that the addition of TMTX to 5-fluorouracil/leucovorin should be investigated further. The possibility that TMTX may both exhibit single-agent activity and modulate the effectiveness of other agents makes combination therapy attractive.
Topics: Antimetabolites, Antineoplastic; Breast Neoplasms; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Esophageal Neoplasms; Folic Acid Antagonists; Head and Neck Neoplasms; Humans; Lung Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms; Trimetrexate
PubMed: 9420024
DOI: No ID Found -
Cancer Investigation 1991
Review
Topics: Adult; Aged; Animals; Antineoplastic Agents; Antiprotozoal Agents; Clinical Trials as Topic; Drug Resistance; Female; Folic Acid Antagonists; Humans; Male; Middle Aged; Neoplasms, Experimental; Quinazolines; Trimetrexate
PubMed: 1830825
DOI: 10.3109/07357909109044227 -
The Annals of Pharmacotherapy Feb 1992The primary objective of this article is to introduce readers to the use of a new agent, trimetrexate (TMTX), in the treatment of Pneumocystis carinii pneumonia (PCP).... (Comparative Study)
Comparative Study Review
OBJECTIVE
The primary objective of this article is to introduce readers to the use of a new agent, trimetrexate (TMTX), in the treatment of Pneumocystis carinii pneumonia (PCP). The article also gives the readers an overview of PCP and discusses some of the controversies surrounding it. Pharmacokinetic data and clinical trials are reviewed, as well as adverse effects, drug interactions, and dosage guidelines.
DATA SOURCES
A MEDLINE search was used to identify pertinent literature, including reviews.
STUDY SELECTION
As both pharmacokinetic and clinical trials were few in number, all available trials were reviewed.
DATA EXTRACTION
Pharmacokinetic data from trials involving patients with AIDS was sparse; therefore, those involving oncology patients, including a pediatric population, were included. Although more trials need to be done in AIDS patients, the results from the oncologic trials give us a baseline from which to extrapolate. All clinical trials available at the time of publication were reviewed as were all of the preliminary results from three ongoing trials, which were made available through a personal communication.
DATA SYNTHESIS
TMTX has been found to be 1500 times more potent than trimethoprim as a dihydrofolate reductase inhibitor, and has the potential to provide an effective therapeutic option for PCP. TMTX is a lipid-soluble analog of methotrexate and is thus capable of greater penetration into Pneumocystis cells, which lack the folate membrane transport system necessary to take up classic folate structures like leucovorin and methotrexate, thereby negating any clinical effectiveness of methotrexate and allowing leucovorin to be used for host cell rescue. TMTX's pharmacokinetic parameters best fit a multicompartmental model with a terminal half-life of up to 12 hours. It is cleared both hepatically and renally with up to 41 percent excreted unchanged in the urine. Although TMTX's pharmacokinetic parameters are variable, the need for plasma concentration monitoring at present is unclear, as no dose-response relationship has been established.
Topics: Acquired Immunodeficiency Syndrome; Humans; Pneumonia, Pneumocystis; Trimethoprim, Sulfamethoxazole Drug Combination; Trimetrexate
PubMed: 1532518
DOI: 10.1177/106002809202600217 -
Seminars in Oncology Oct 2000
Review
Topics: Antidotes; Antimetabolites, Antineoplastic; Clinical Trials as Topic; Colorectal Neoplasms; Fluorouracil; Folic Acid Antagonists; Humans; Leucovorin; Trimetrexate
PubMed: 11049038
DOI: No ID Found