Journal article
EFFECT OF THYMIDINE ON THE TOXICITY, ANTI-TUMOR ACTIVITY, AND METABOLISM OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE IN RATS BEARING A CHEMICALLY-INDUCED COLON-CARCINOMA
Cancer research (Chicago, Ill.), Vol.40(4), pp.1274-1280
01/01/1980
PMID: 7357557
Abstract
The effect of thymidine (dThd) on the toxicity, antitumor activity against colon carcinoma, and metabolism of 1-β-d-arabinofuranosylcytosine (ara-C) in female Fischer rats was evaluated utilizing continuous i.v. infusion of these agents into the tail vein of unrestrained rats. Treatment of normal rats with a 24-hr infusion of dThd (7.0 g/kg/day) followed by coadministration of dThd with ara-C for 48 hr resulted in a 35-fold augmentation of the toxicity of ara-C. In rats bearing s.c. implanted colon carcinoma, a slightly superior inhibition of tumor growth occurred when ara-C was administered at the maximally tolerated dose following a 24-hr infusion with dThd than when ara-C was given with no prior dThd. However, no significant increase in life span over control was observed using ara-C alone or in combination with dThd, with or without dThd pretreatment.
Analysis of rat plasma by high-pressure liquid chromatography revealed that treatment with dThd by continuous infusion and not by i.v. bolus injection produced a dramatic reduction in the circulating level of deoxycytidine from 21.8 ± 4.6 (S.D.) to 4.4 ± 0.6 µm within 24 hr following the initiation of infusion.
The in vivo metabolism of ara-C following i.v. bolus administration of [5-3H]ara-C to 0.9% NaCl solution- or dThd-infused rats was also studied. High-pressure liquid chromatography analysis of the acid-soluble fractions of tumor and of various host tissues from these rats showed that the intracellular levels of 1-β-d-arabinofuranosylcytosine 5′-triphosphate were greater in the rats infused with dThd than were those in 0.9% NaCl solution controls and varied from 7- to 1830-fold over controls in the order of bone marrow > tumor > intestines > spleen > liver. The increase in ara-C incorporation into nucleic acid fractions was also in the same direction and was greater when dThd treatment preceded ara-C.
These data suggest that modulation of the plasma levels of deoxycytidine by dThd as well as the enhanced intracellular activation of ara-C to 1-β-d-arabinofuranosylcytosine 5′-triphosphate following infusion of dThd may account in part for enhanced tumor and host sensitivities to ara-C.
Details
- Title: Subtitle
- EFFECT OF THYMIDINE ON THE TOXICITY, ANTI-TUMOR ACTIVITY, AND METABOLISM OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE IN RATS BEARING A CHEMICALLY-INDUCED COLON-CARCINOMA
- Creators
- L L DanhauserY M Rustum
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.40(4), pp.1274-1280
- Publisher
- Amer Assoc Cancer Research
- PMID
- 7357557
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Number of pages
- 7
- Language
- English
- Date published
- 01/01/1980
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359877702771
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