Hammond W G, Yellin A, Gabriel A, Paladugu R R, Azumi N, Hill L R, Benfield J R
Department of Thoracic Surgery, City of Hope National Medical Center, Duarte, California 91010.
Exp Mol Pathol. 1990 Aug;53(1):34-51. doi: 10.1016/0014-4800(90)90022-6.
5-Azacytidine (AZC) was studied in a lung cancer model in outbred and syngeneic (F1D) hamsters wherein benzol[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 F1D 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 F1D 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 incidence 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.
在远交系和同基因（F1D）仓鼠的肺癌模型中对5-氮杂胞苷（AZC）进行了研究，在该模型中，来自缓释植入物（SRI）的苯并[a]芘（BP）会诱发癌前黏膜变化，并发展为支气管源性癌。在评估AZC毒性的初步研究中，发现每两周5 mg/kg的给药方案是合适的，随后在所有后续研究中都采用该方案进行长期给药。研究了三组远交系仓鼠：单独使用BP SRI（n = 60）、BP SRI + AZC（n = 60）和单独使用AZC（n = 54）。在植入SRI后3 - 5天开始进行AZC治疗。实验开始61天后，每组处死7或8只仓鼠。在接受BP SRI的组中，后续处死间隔为3周，而在仅使用AZC的组中，间隔为6周。研究了四组F1D同基因仓鼠：单独使用BP SRI（n = 50）；在植入SRI后3 - 5天开始使用BP + AZC并持续至死亡（n = 52）；在植入SRI后3至5天至75天使用BP + AZC（n = 49）；在植入SRI后80天开始使用BP + AZC并持续至死亡（n = 52）。在植入SRI后120、150、180和220天，每组处死9 - 14只仓鼠。在这些条件下，单独使用AZC不具有致癌性。与单独接受BP SRI或BP +晚期AZC的动物相比，接受早期或持续AZC治疗的远交系和F1D仓鼠由BP SRI引起的肿瘤性变化速率较慢。所有治疗方案的表皮样癌发生率相同，但在致癌过程早期接受AZC的动物中的肿瘤比接受晚期AZC或未接受AZC的动物中的肿瘤小。在致癌早期接受AZC的动物中，非表皮样癌的发生率较低，而在未使用AZC的情况下观察到更大的肿瘤。因此，在这个独特的仓鼠肺癌模型的研究期间，在致癌早期给予AZC仅抑制了BP表皮样癌发生的后期（促进）阶段，但抑制了BP诱导的非鳞状癌发展的所有阶段。这种在癌前阶段给予AZC所产生的支气管癌发生的差异调节，可能有助于阐明支气管源性癌特定表型类型背后的分子机制。
