The Combined Effects of Hydroxyurea and X Irradiation on Murine Duodenal Mucosa and Host Survival

• Published in: Radiation research 1980-06, Vol.82 (3), p.518-525
• Main Authors: Dethlefsen, L. A., Ohlsen, J. D., Riley, R. M.
• Format: Article
• Language: English
• Subjects: Animals; Cell Survival - drug effects; Cell Survival - radiation effects; Circumferences; Crypts; DNA - metabolism; DNA - radiation effects; Dosage; Duodenum - drug effects; Duodenum - radiation effects; Embryonic cells; Epithelial cells; Female; Hydroxyurea - administration & dosage; Hydroxyurea - pharmacology; Injections, Intraperitoneal; Interphase - drug effects; Interphase - radiation effects; Intestinal Mucosa - drug effects; Intestinal Mucosa - radiation effects; Irradiation; Kinetics; Lethal Dose 50; Male; Mice; Mice, Inbred C3H; Radiation Dosage; Radiation tolerance; Radiation-Protective Agents - administration & dosage; Radiotherapy; Time Factors; X-Rays
• ISSN: 0033-7587; 1938-5404
• DOI: 10.2307/3575318

The duodenal response to X irradiation, in terms of both crypt survival (D0 and 10-clone dose) and host toxicity (${\rm LD}_{50/6}$), has been evaluated as a function of time of X irradiation after either a single injection of hydroxyurea (3 mg/g body wt) or five injections (0.5 mg/g followed at 1-hr intervals by four injections of 0.25 mg/g each). The data indicate that the five-injection protocol is more effective than a single injection at accumulating proliferating crypt cells at the G1/ S interface and that the initial cohort of S-phase cells after the hydroxyurea release is more radioresistant than the exponentially distributed population of proliferating crypt cells ($D_{0}\simeq 220$ rad vs control $D_{0}\simeq 150$ rad). The duodenal crypt cells X-irradiated 1 hr after the last hydroxyurea injection (both protocols), when they are still blocked at the G1/ S interface, are also more radiosensitive ($D_{0}\simeq 100$ rad) than control crypt cells. This is apparently due to a chemical radiosensitization by the hydroxyurea still present in the serum of the mice. A comparison of the 10-clone dose to the ${\rm LD}_{50/6}$ dose indicates that there is an "uncoupling" of crypt survival from the so-called "clinical endpoint" of host toxicity in such a combined-modality protocol. This suggests that, when a systemic cell-cycle phase-specific agent is used in combination with whole-abdomen irradiation, crypt survival per se is only one important variable contributing to the classic gastrointestinal death syndrome.