Evaluation of the antitumor activity of gemcitabine (2',2'-difluoro-2'-deoxycytidine)

A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in t...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1990-07, Vol.50 (14), p.4417-4422
Main Authors: HERTEL, L. W, BODER, G. B, KROIN, J. S, RINZEL, S. M, POORE, G. A, TODD, G. C, GRINDEY, G. B
Format: Article
Language:English
Subjects:
Animals
Antimetabolites, Antineoplastic - therapeutic use
Antineoplastic agents
Biological and medical sciences
Cell Line
Cell Survival - drug effects
Chemotherapy
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Deoxycytidine - therapeutic use
Deoxycytidine - toxicity
Drug Evaluation, Preclinical
Drug Screening Assays, Antitumor
Female
Flow Cytometry
Humans
Leukemia L1210 - drug therapy
Leukemia P388 - drug therapy
Leukemia, Experimental - drug therapy
Male
Medical sciences
Mice
Mice, Inbred ICR
Mice, Inbred Strains
Neoplasms, Experimental - drug therapy
Pharmacology. Drug treatments
Tumor Cells, Cultured - cytology
Tumor Cells, Cultured - drug effects
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Summary:A new pyrimidine antimetabolite, 2',2'-difluorodeoxycytidine, Gemcitabine (LY188011, dFdCyd) has been synthesized and evaluated in experimental tumor models. dFdCyd is a very potent and specific deoxycytidine analogue. The concentration required for 50% inhibition of growth is 1 ng/ml in the CCRF-CEM human leukemia cell culture assay. Concurrent addition of deoxycytidine to the cell culture system provides about a 1000-fold decrease in biological activity. The inhibition of growth of human leukemia cells in culture led to the in vivo evaluation of this compound as a potential oncolytic agent. Maximal activity in vivo was seen with dFdCyd when administered on an every third day schedule. 1-beta-D-Arabinofuranosylcytosine, administered on a daily for 10-day schedule, was directly compared to dFdCyd in this evaluation. dFdCyd demonstrated good to excellent antitumor activity in eight of the eight murine tumor models evaluated. 1-beta-D-Arabinofuranosylcytosine was substantially less active or had no activity in these same tumor models. This in vivo activity against murine solid tumors supports the conclusion that dFdCyd is an excellent candidate for clinical trials in the treatment of cancer.
ISSN:0008-5472
1538-7445