Effects of 5-azacytidine in syrian golden hamsters: Toxicity, tumorigenicity, and differential modulation of bronchial carcinogenesis

Abstract

5-Azacytidine (AZC) was studied in a lung cancer model in outbred and syngeneic (F 1D) hamsters wherein benzo[ a]pyrene (BP) from sustained release implants (SRI) induces preneoplastic mucosal changes which progress to bronchogenic cancer. In pilot studies to evaluate AZC toxicity, a dose schedule of 5 mg/kg biweekly was found suitable and was then used for long-term administration in all subsequent studies. Three groups of outbred hamsters were studied: BP SRI alone ( n = 60), BP SRI + AZC ( n = 60), and AZC alone ( n = 54). AZC treatment was begun 3–5 days after SRI placement. Sixty-one days after the start of the experiment, seven or eight hamsters were sacrificed from each group. Later sacrifices were at 3-week intervals in groups receiving BP SRI and at 6-week intervals in the AZC only group. Four groups of F 1D syngeneic hamsters were studied: BP SRI alone ( n = 50); BP + AZC starting 3–5 days after SRI placement and continuing until death ( n = 52); BP + AZC from 3 to 5 days until 75 days after SRI placement ( n = 49); BP + AZC starting 80 days after SRI placement and continuing until death ( n = 52). Hamsters ( n = 9–14) from each group were sacrificed at 120, 150, 180, and 220 days after SRI implantation. AZC alone was not carcinogenic under these conditions. Both outbred and F 1D hamsters treated with early or continuous AZC had slower rates of neoplastic change from BP SRI than did animals receiving BP SRIs alone or BP + late AZC. The incidences of epidermoid cancer were the same for all regimens, but the tumors in those receiving AZC early in carcinogenesis were smaller than in those receiving late or no AZC. The incidences of nonepidermoid cancer were lower in those receiving AZC during early carcinogenesis, and larger tumors were noted in the absence of AZC. Thus, within the study period in this unique hamster lung cancer model, AZC given early in carcinogenesis inhibited only the later (promotional) phase of BP epidermoid carcinogenesis, but inhibited all phases of nonsquamous cancer development induced by BP. This differential modulation of bronchial carcinogenesis, which occurs from AZC given during preneoplastic stages, may prove useful for delineating molecular mechanisms underlying specific phenotypic types of bronchogenic cancers.