Acquired Radioresistance of Transplanted Mammary Adenocarcinoma in Inbred Mice after Serial Irradiation

The clinical phenomenon of acquired radioresistance has long been a controversial problem in radiotherapy. That cancer of the corpus uteri which had recurred after radiotherapy was unresponsive to further treatment was first noted in 1904 by Lasseur (cf. 22). Lacassagne (11) reported the disappearance of clinical disease in only 4 of 73 cases of recurrent uterine cancers, whereas 20 per cent of the tumors treated initially were cured. Numerous other examples of increased radioresistance following previous radiotherapy were reviewed by Windeyer (28). In 1956, Murphy and Schmitz reported that only 9 of 46 patients re-irradiated for cancer of the cervix were alive six years later (13). Kramer (10) stated in 1962 that re-irradiation of cancers of the head and neck should be undertaken only after rigid patient selection. Attempts to mimic acquired radioresistance in experimental animals have yielded equivocal results. Snellman (22) irradiated the Jensen rat sarcoma in vivo and, following serial transplantation and irradiation, demonstrated reduced radiation response. Conger and Luippold (5) failed to observe any change in radiation response as measured by induced chromsome aberrations in Ehrlich ascites carcinoma following continuous irradiation at various exposure rates. Révész and Norman (19), however, showed that the radiation response with respect to the number of Ehrlich ascites tumor cells present in an intraperitoneally implanted diffusion chamber is decreased following serial preirradiation. Results of numerous other animal experiments have been equally conflicting. Hypotheses proposed to explain acquired radioresistance can be classified into two general categories: those based on changes in the tumor cell population, and those based on changes in the host. One in the first states that, assuming heterogeneity in the radiosensitivity of the cells within a tumor, only the more radiosensitive cells would be removed from the population by inadequate treatment, leaving the more radioresistant ones to give rise to recurrent tumor (8, 30). Another more specifically implicates a change in the deoxyribonucleic acid (DNA) content of the tumor cells following preirradiation. Atkin and Richards (1, 20) demonstrated an increase in the cellular DNA content and a decrease in the radiation response of human cervical cancer following radiation therapy, and Pearson and Atkin (15) confirmed these results in mouse sarcoma 37. They also reported a reduced radiation response in carcinomas of higher than diploid chromosome mode, although observations of other experimenters on the effect of ploidy on tumor radiosensitivity have been inconsistent (9, 18, 26). It is possible that the first radiation exposure could induce somatic mutations causing increased radioresistance in some tumor cells. Direct evidence in support of this postulate is not available.