Paradoxical effect of aspirin on the growth of C6 rat glioma and on time of development of ENU-induced tumors of the nervous system

Purpose: Administration of acetylsalicylic acid (ASA), an inhibitor of the synthesis of prostaglandins and thrombzoxanes, decreases the incidence of c olorectal cancer and other neoplasms and inhibits in vitro some tumor growt h. We studied the effect of various doses of ASA on the growth of C6 glioma implanted in rats as well as the effect of chronic administration of ASA o n time of development and incidence of tumors of the central nervous system (CNS) induced by prenatal exposure to ethylnitrosourea (ENU). Methods: In a controlled study, various doses of ASA, 12.5, 25, 50, 100, 200, 300, and 400 mg/kg per day, were administered to Wistar rats in whom a subcutaneous C6 glioma had been transplanted. Changes in tumor size, histologic characte ristics, mitotic index, cell proliferation, and vascular density were studi ed. In a parallel experiment, we administered ASA (70 mg/kg per day) to rat s who were prenatally exposed to ENU; treatment started on day 50 of age, a nd continued until the end of the experiment at day 400. The time of tumor development as well as incidence, localization, and histological diagnosis were compared with matched controls. Results: A paradoxical effect of ASA a dministration was observed on the dynamics of cell proliferation of C6 glio ma. When high ASA doses were administered (200 or 400 mg/kg per day), tumor volume, cell proliferation, vascular density, and mitotic index increased. In contrast, when low doses were administered (12.5 or 25 mg/kg per day) t he tumor size diminished. In the second experiment, localization and incide nce of CNS tumors induced by ENU were similar in animals treated with ASA a nd in controls; however, in rats treated with ASA the time of tumor develop ment was shortened. Conclusions: The growth-promoting effects of high doses of ASA found in the present study in both transplanted and chemically-indu ced brain tumors, might be due to the blockage of autocrine inhibitory fact ors dependent on the cyclooxygenase pathway or by increased vascular permea bility and blood supply to the tumor due to inhibition of platelet aggregat ion. In contrast, the inhibition of tumor growth obtained with low ASA dose s in transplanted glioma might be due to different mechanisms such as the i nduction of apoptosis.