Document Detail

Phase I trial of N-(phosphonacetyl)-L-aspartate, methotrexate, and 5-fluorouracil with leucovorin rescue in patients with advanced cancer.
MedLine Citation:
PMID:  2472883     Owner:  NLM     Status:  MEDLINE    
Based on an animal model to improve the antitumor activity of 5-fluorouracil (FUra), a Phase I study of N-(phosphonacetyl)-L-aspartate, methotrexate, FUra, and leucovorin was conducted on 44 patients. Methotrexate was given in an intermediate dose (250 mg/m2) to overcome potential drug resistance, and N-(phosphonacetyl)-L-aspartate was given at a low dose (250 mg/m2) in order to allow escalation of FUra to toxicity. These two drugs were given 24 h before FUra to enhance maximal incorporation of FUra into RNA. Two schedules of administration were used; one every other week and one weekly for 2 weeks. The every other week schedule was well tolerated, with minimal gastrointestinal and hematological toxicity. However, the weekly for 2 weeks schedule was more toxic with increased mucositis, diarrhea requiring therapy, and decreased performance status of 20% in 4 of 6 patients. There were no responders in the every other week schedule. There was one partial response and three patients with stable disease in four evaluable patients on the weekly for 2 weeks schedule. At 24 h post-N-(phosphonacetyl)-L-aspartate-methotrexate treatment, PRPP levels were doubled in bone marrow biopsies, and increased 2.5- to 25-fold in tumor biopsies. We have currently added uridine rescue to this combination with the hope of further escalating the dose of FUra.
N Kemeny; A Schneider; D S Martin; J Colofiore; R C Sawyer; S Derby; B Salvia
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer research     Volume:  49     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  1989 Aug 
Date Detail:
Created Date:  1989-08-23     Completed Date:  1989-08-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4636-9     Citation Subset:  IM    
Department of Developmental Chemotherapy, Memorial Sloan Kettering Cancer Institute, New York 10021.
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MeSH Terms
Adenocarcinoma / drug therapy*,  pathology
Antineoplastic Agents / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Aspartic Acid / administration & dosage,  analogs & derivatives
Bone Marrow / analysis
Carcinoma, Squamous Cell / drug therapy*,  pathology
Colorectal Neoplasms / drug therapy*,  pathology
Drug Administration Schedule
Drug Evaluation
Fluorouracil / administration & dosage,  adverse effects,  analysis,  antagonists & inhibitors
Head and Neck Neoplasms / drug therapy*,  pathology
Leucovorin / therapeutic use
Methotrexate / administration & dosage
Pentosephosphates / blood
Phosphonoacetic Acid / administration & dosage,  analogs & derivatives
Phosphoribosyl Pyrophosphate
Grant Support
Reg. No./Substance:
0/Antineoplastic Agents; 0/Pentosephosphates; 4408-78-0/Phosphonoacetic Acid; 51-21-8/Fluorouracil; 51321-79-0/NSC 224131; 56-84-8/Aspartic Acid; 58-05-9/Leucovorin; 59-05-2/Methotrexate; 7540-64-9/Phosphoribosyl Pyrophosphate

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