Borsellino N, Crescimanno M, Flandina C, Leonardi V, Rausa L, D'Alessandro N
Istituto di Farmacologia, Facoltà di Medicina e Chirurgia, Università di Palermo, Policlinico P. Giaccone, Italy.
Anticancer Drugs. 1993 Apr;4(2):265-72. doi: 10.1097/00001813-199304000-00020.
Biological agents might offer various therapeutic opportunities in the treatment of cancer, including a direct and/or host-mediated antiproliferative effect and also the possibility to favorably modulate tumor resistance to antineoplastic drugs. We studied the in vitro antiproliferative effects of interferon (IFN)-gamma on the mouse B16 melanoma and Friend erythroleukemia, and the human K562 erythroleukemia, as doxorubicin (DXR)-sensitive and -resistant (multidrug resistant) variants. These effects were marked in B16 melanoma and rather slight in K562 erythroleukemia, without any difference between the DXR-sensitive and -resistant lines. The chemosensitive variant of Friend erythroleukemia showed an intermediate response, which was greater than that seen in its resistant counterpart. There was no apparent relationship between the antiproliferative activity of IFN-gamma and the glutathione content of the cell lines. On the other hand, this activity was enhanced by co-treatment with glutathione-depleting concentrations of buthionine sulfoximine, but only in the cell lines which had responded better to IFN-gamma alone. This result probably confirms that a free radical mechanism plays a part in the antitumor effect of the cytokine. Finally, a range of concentrations of IFN-gamma, including slightly cytotoxic ones, did not substantially improve the antiproliferative effects of doxorubicin on the various cell lines, except in the DXR-sensitive variant of Friend erythroleukemia where a synergistic effect of the combination was observed. Thus, our results are not very promising with regard to a possible favorable modulatory activity by IFN-gamma of DXR (multidrug)-resistance.
生物制剂在癌症治疗中可能提供多种治疗机会，包括直接和/或宿主介导的抗增殖作用，以及有利地调节肿瘤对抗肿瘤药物耐药性的可能性。我们研究了干扰素（IFN）-γ对小鼠B16黑色素瘤和Friend红白血病以及人K562红白血病（作为阿霉素（DXR）敏感和耐药（多药耐药）变体）的体外抗增殖作用。这些作用在B16黑色素瘤中很明显，而在K562红白血病中相当轻微，DXR敏感和耐药细胞系之间没有任何差异。Friend红白血病的化学敏感变体表现出中等反应，大于其耐药对应物的反应。IFN-γ的抗增殖活性与细胞系的谷胱甘肽含量之间没有明显关系。另一方面，与谷胱甘肽消耗浓度的丁硫氨酸亚砜胺共同处理可增强这种活性，但仅在对单独的IFN-γ反应较好的细胞系中。这一结果可能证实自由基机制在细胞因子的抗肿瘤作用中起作用。最后，一系列浓度的IFN-γ，包括轻度细胞毒性浓度，除了在Friend红白血病的DXR敏感变体中观察到联合用药的协同作用外，并没有实质性地改善阿霉素对各种细胞系的抗增殖作用。因此，就IFN-γ对DXR（多药）耐药性可能具有的有利调节活性而言，我们的结果不太乐观。
