Delayed enhanced effects of Adriamycin on the X-irradiation-induced gastrointestinal toxicity in mice

The delayed responses of C3H mice which had been pretreated with various single-dose and two-dose fractionated Adriamycin/X-irradiation protocols were evaluated by stressing the 120-day survivors with either whole-abdomen X-irradiation (LD50/7 assay) or whole-body X-irradiation (crypt colony survival). Pretreatment with Adriamycin alone was as toxic as Adriamycin plus X-irradiation for the animals stressed at 120 days (LD50/7 assay). There was no induced cellular radioresistance (D0) and no apparent increase in crypt size as indicated indirectly by the 10-clone dose at 120 days after completion of treatment. The increased lethality of the X-irradiation-stressed 120-day survivors was most likely a primary gastrointestinal response with little or no contribution from either bone marrow or kidney toxicity. The effect was apparently due to a persistent Adriamycin-induced antiproliferative response at the cellular level but the molecular mechanisms are unknown. Such data suggest caution to our clinical colleagues. Cancer patients treated with high doses of Adriamycin, independent of concomitant X-irradiation, will most likely be moderately to severely compromised in their ability to respond to a stress which requires cellular proliferation, and, based on the murine data, this effect is persistent if, indeed, not permanent.