Tumorigenesis in High-Dose Total Body Irradiated Rhesus Monkeys—A Life Span Study

Abstract

In the early sixties, studies have been performed at the TNO-Institutes for Health Research on acute effects of high dose total body irradiation (TBI) with X-rays and fission neutrons in Rhesus monkeys and the protective effect of autologous bone marrow transplantation (BMT). The surviving animals of this study were kept to investigate late radiation effects, ie, tumorigenesis. TBI in combination with chemotherapy, followed by rescue with BMT is increasingly used for the treatment of hematological malignancies and refractory autoimmune disease. The risk of radiation carcinogenesis after this treatment is of growing concern in man. Studies on tumor induction in nonhuman primates are of relevance in this context since the response of this species to radiation does not differ much from that in man. The group of long-term surviving monkeys comprised nine neutron irradiated animals (average total body dose 3.4 Gy, range 2.3—4.4 Gy) and 20 X-irradiated monkeys (average total body dose 7.1 Gy, range 2.8—8.6 Gy). A number of 21 age-matched nonirradiated Rhesus monkeys served as a control-group. All animals were regularly screened for the occurrence of tumors. Complete necropsies were performed after natural death or euthanasia. At postirradiation intervals of 4—21 years an appreciable number of malignant tumors was observed. In the neutron irradiated group eight out of nine animals died with 1 or more malignant tumors. In the X-irradiated group this fraction was 10 out of 20. The tumors in the control group, in seven out of 21 animals, appeared at much older age compared with those in the irradiated cohorts. The histogenesis of the malignant tumors was diverse, as was the case for benign tumors. The observed shortening of latency periods and life span, as well as, the increase of mean number of tumors per tumor bearing animal for benign neoplasms parallels the trend observed for malignant tumors. The results of this study were compared to other radiation late effects after TBI followed by different BMT treatment modalities in Rhesus monkeys. The observation that the carcinogenic risk of TBI in the Rhesus monkeys is similar to that derived from the studies of the Japanese atomic bomb survivors and the increase of the risk by a factor of 8 emphasizes the need for regular screening for secondary radiation-induced tumors in long-term surviving patients after TBI followed by BMT.