Journal article
Polyglutamylation of the dihydrofolate reductase inhibitor γ-methylene-10-deazaaminopterin is not essential for antitumor activity
Clinical cancer research, Vol.2(4), pp.707-712
1996
PMID: 9816221
Abstract
As part of a continuing program aimed at developing nonpolyglutamylatable inhibitors of dihydrofolate reductase that are less toxic and more specific in their action, we herein report the therapeutic efficacy and toxicity of gamma-methylene-10-deazaaminopterin (MDAM) in athymic nude mice bearing advanced human HCT-8 ileocecal xenografts and its antitumor activity in C57BL/6 x DBA/2 F1 (hereafter called B6D2F1) mice bearing P388 murine leukemia. For the xenograft study, MDAM was administered at the maximum tolerated dose by the following dose schedules: (a) 5-day continuous i.v. infusion at 1.0 mg/kg/day (schedule I); and (b) i.v. push, daily for 5 days at 50 mg/kg/day (schedule II). The maximum tolerated dose values for methotrexate (MTX) under these conditions were 0.2 and 1.0 mg/kg/day for schedule I and schedule II, respectively. MTX did not exhibit any significant antitumor activity in this model system by both schedules; however, MDAM induced complete responses of 13 and 25% and partial responses of 25 and 50% by schedules I and II, respectively. MDAM also exhibited antitumor activity significantly superior to that of MTX in the P388 tumor model. One of the enantiomers of MDAM, which possesses the natural configuration at the gamma-methyleneglutamate moiety (l-MDAM), has been shown to be a better inhibitor of human recombinant dihydrofolate reductase and H35 hepatoma cell growth than D,L-MDAM. L-MDAM inhibited the uptake of radiolabeled folinic acid to H35 hepatoma cells eight times more efficiently than MTX. The results indicate that the superior activity of MDAM relative to MTX may be partially due to a combination of enhanced transport to tumor cells and slower deactivation by aldehyde oxidase.
Details
- Title: Subtitle
- Polyglutamylation of the dihydrofolate reductase inhibitor γ-methylene-10-deazaaminopterin is not essential for antitumor activity
- Creators
- S Cao - Roswell Park Cancer InstituteA Abraham - Roswell Park Cancer InstituteM. G Nair - Roswell Park Cancer InstituteR Pati - Roswell Park Cancer InstituteJ. H Galivan - Roswell Park Cancer InstituteF. H Hausheer - Roswell Park Cancer InstituteY. M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.2(4), pp.707-712
- Publisher
- American Association for Cancer Research
- PMID
- 9816221
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Language
- English
- Date published
- 1996
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984360048402771
Metrics
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