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Increasing evidence suggests a role for reactive free radical oxygen species in the multi-stage events of chemical carcinogenesis. We hypothesized that variations in the level of superoxide dismutase (SOD), a major endogenous antioxidant enzyme, may account in part for variations in susceptibility to cancer induced by polycyclic aromatic hydrocarbons (PAH). The SOD activity of mammary epithelial cells from rats with varying susceptibility to dimethylbenz[a]anthracene (DMBA)-induced breast cancer was assayed. Ageing, pregnancy and previous multiple pregnancies reduce susceptibility of Sprague--Dawley female rats to DMBA. These decreases in susceptibility were correlated with increased levels of SOD activity. Only minor differences in SOD activity was observed in mammary epithelium of genetic strains of rats with differences in susceptibility to DMBA. These data suggest that, in models where physiological differences may account for variations in effectiveness of PAH to induce mammary cancer, SOD activity is inversely correlated with breast cancer susceptibility and support the hypothesis that cancer susceptibility may be partially mediated through reactive free radical oxygen intermediates.

Our previous studies suggested that a defect in the hemopoietic microenvironment of bone marrow occurred in the anemia of chronic inflammatory disease. We examined the in vivo hemopoietic and marrow stromal cell (MSC) response of shielded marrow to 5000 rad leg-irradiation (5000 rad LI), the in vitro growth of BFUE, CFUE, and CFUC in co-culture with MSC, and the in vitro characteristics of MSC. One month after 5000 rad LI, erythroblasts and MSC fell to 18% and 26% respectively. BFUE and CFUE in shielded marrow increased 1.5 to 2 times. Total CFUS and CFUC were normal. In co-culture, small numbers of MSC enhanced BFUE and CFUE, but suppressed CFUC. MSC in colonies were polygonal cells with a plating efficiency of 10 per 10(6) nucleated marrow cells and 1 per 10(6) spleen or nucleated blood cells. MSC were not phagocytic and did not stain with nonspecific esterase. We conclude that in mice with an inflammatory response to 5000 rad LI: 1) Erythroblasts and MSC decreased while erythroid progenitors (BFUE and CFUE) increased in the shielded marrow, 2) MSC stimulated BFUE and CFUE in co-culture, 3) MSC in colonies were adherent, large polygonal cells that may enhance erythroid maturation in the bone marrow.

Hemopoietic insufficiency resulting from single or multiple agents used in cancer therapy often becomes a dose limiting toxicity. Since hyperthermia is finding increased clinical application with whole body or extended field treatments for a variety of neoplastic diseases, we wished to examine its potential effects on normal bone marrow. One hind leg of anesthetized mice received up to one hour water bath heating to 41-44 degrees C. With temperatures of 42 degrees C or greater, there was a dose and heating time dependent initial depletion of both CFU-S and CFU-GM that was not appreciably affected by migration of stem cells to or from the heated field. CFU-S and CFU-GM returned to normal values by 2 to 3 weeks after 1 hour heating to 42 degrees C. However, at 43 degrees or 44 degrees C for 1 hour, CFU-GM only transiently returned to normal, falling to 55% and 33% of control respectively by 3 months. Total nucleated cell counts reflected a similar dose and time dependent depletion and repopulation. Finally, bone marrow differential counts from heated marrow suggested that equivalent repopulation along each differentiation pathway occurred during recovery after thermal injury. These data indicate that temperatures greater than 42 degrees C for one hour caused a long term delay in hemopoietic repopulation, which may contribute to a significant toxicity when hyperthermia is used in combination with chemotherapeutic drugs or local irradiation incorporating the same treatment field.