Paradoxical effect of aspirin on the growth of C6 rat glioma and on time of development of ENU-induced tumors of the nervous system.
OBJECTIVE
Administration of acetylsalicylic acid (ASA), an inhibitor of the synthesis of prostaglandins and thrombzoxanes, decreases the incidence of colorectal cancer and other neoplasms and inhibits in vitro some tumor growth. 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 on 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 characteristics, mitotic index, cell proliferation, and vascular density were studied. In a parallel experiment, we administered ASA (70 mg/kg per day) to rats who were prenatally exposed to ENU; treatment started on day 50 of age, and 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 administration was observed on the dynamics of cell proliferation of C6 glioma. 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) the tumor size diminished. In the second experiment, localization and incidence of CNS tumors induced by ENU were similar in animals treated with ASA and in controls; however, in rats treated with ASA the time of tumor development was shortened.


CONCLUSIONS
The growth-promoting effects of high doses of ASA found in the present study in both transplanted and chemically-induced brain tumors, might be due to the blockage of autocrine inhibitory factors dependent on the cyclooxygenase pathway or by increased vascular permeability and blood supply to the tumor due to inhibition of platelet aggregation. In contrast, the inhibition of tumor growth obtained with low ASA doses in transplanted glioma might be due to different mechanisms such as the induction of apoptosis.
Arrieta
O
O
Neuroimmunology Unit, Instituto Nacional de Neurologia y Neurocirugía and Instituto de Investigaciones Biomédicas, Mexico City, Mexico. ogar@servidor.unam.mx
Guevara
P
P
Reyes
S
S
Palencia
G
G
Rivera
E
E
Sotelo
J
J
D000477:Alkylating Agents; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology*; D002273:Carcinogens; D002455:Cell Division; D016543:Central Nervous System Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005038:Ethylnitrosourea; D005910:Glioma / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002273:Carcinogens; D005038:Ethylnitrosourea; D001241:Aspirin