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Folylpolyglutamate synthetase inactivation in relapsed ALL induces a druggable folate metabolic vulnerability.
Drug Resist Updat
November 2024
Pediatric Translational Medicine Institute, Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Fujian Children's Hospital, Fujian Branch of Shanghai Children's Medical Center Affiliated to Shanghai Jiao Tong University School of Medicine, Fuzhou, China; Department of Pharmacology and Chemical Biology, School of Basic Medicine and Shanghai Collaborative Innovation Center for Translational Medicine Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address:
Aims: The antifolate methotrexate (MTX) is an anchor drug used in acute lymphoblastic leukemia (ALL) with poorly understood chemoresistance mechanisms in relapse. Herein we find decreased folate polyglutamylation network activities and inactivating FPGS mutations, both of which could induce MTX resistance and folate metabolic vulnerability in relapsed ALL.
Methods: We utilized integrated systems biology analysis of transcriptomic and genomic data from relapse ALL cohorts to infer hidden ALL relapse drivers and related genetic alternations during clonal evolution.
S9511: a Southwest Oncology Group phase II study of trimetrexate, 5-fluorouracil, and leucovorin in unresectable or metastatic adenocarcinoma of the stomach.
Am J Clin Oncol
April 2010
Division of Medical Oncology, University of British Columbia and British Columbia Cancer Agency, Vancouver, BC.
Objective: The primary objective of this trial was to evaluate the response rate for trimetrexate in conjunction with 5-FU and leucovorin (LV) (= TFL) in the treatment of advanced gastric cancer in a phase II, cooperative group setting.
Methods: Patients with locally advanced, unresectable, or metastatic adenocarcinoma of the stomach received trimetrexate 110 mg/m IV over 60 minutes day 1, followed by 5-FU 500 mg/m IV bolus and LV 200 mg/m IV over 60 minutes day 2, followed by oral LV 15 mg every 6 hours x 7 doses, all weekly for 6 weeks followed by 2 weeks of rest, continued until progression.
Results: Characteristics for 37 eligible patients: median age 63 (range: 23-83); male/female: 69% of 31%; performance status 0/1/2 15/20/1.
Double modulation of 5-fluorouracil by trimetrexate and leucovorin in patients with advanced colorectal carcinoma.
Am J Clin Oncol
April 2004
Grupo Oncológico Cooperativo del Sur, Neuquen, República Argentina.
The purpose of this report is to evaluate the efficacy and toxicity (Tx) of a double modulation of 5-fluorouracil (5-FU) by trimetrexate (TMTX) and leucovorin (LV) in patients with advanced recurrent (inoperable) or metastatic colorectal cancer (ACC). Between December 1997 and August 2000, 36 patients were entered in this phase II study. Median age was 61 years, and 18 patients (50%) were female.
View Article and Find Full Text PDFA new nonlinear mixture response surface paradigm for the study of synergism: a three drug example.
Curr Drug Metab
October 2003
Departments of Mathematics and Pharmacology, The University of Toledo, Toledo, OH 43606, USA.
A flexible approach to response surface modeling for the study of the joint action of three active anticancer agents is used to model a complex pattern of synergism, additivity and antagonism in an in vitro cell growth assay. The method for determining a useful nonlinear response surface model depends upon a series of steps using appropriate scaling of drug concentrations and effects, raw data modeling, and hierarchical parameter modeling. The method is applied to a very large in vitro study of the combined effect of Trimetrexate (TMQ), LY309887 (LY), and Tomudex (TDX) on inhibition of cancer cell growth.
View Article and Find Full Text PDFTrimetrexate in relapsed T-cell lymphoma with skin involvement.
J Clin Oncol
June 2002
Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Purpose: Methotrexate (MTX) is active against lymphomas, but transport or polyglutamylation mutations confer MTX resistance. Because trimetrexate (TMTX) enters cells by passive diffusion and is not polyglutamylated, its activity in relapsed T-cell lymphoma was investigated.
Patients And Methods: Eligible patients had histologically confirmed relapsed T-cell lymphoma involving the skin, had received more than one previous regimen, were older than 16 years, had normal organ function, and had no CNS disease or serious infections, including human immunodeficiency virus.
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