Majewski S, Marczak M, Szmurlo A, Jablonska S, Bollag W
Department of Dermatology, Warsaw School of Medicine, Poland.
Cancer Lett. 1995 Feb 10;89(1):117-24. doi: 10.1016/0304-3835(95)90166-3.
Retinoids combined with interferon alpha-2a (IFN alpha) or 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] have shown marked synergistic inhibitory effects on angiogenesis induced by tumor cell lines harboring DNA of oncogenic human papillomaviruses (HPV) type 16 or 18. This report demonstrates comparable effects of these compounds on angiogenesis induced by non-HPV-bearing transformed cell lines, including breast carcinoma (T47D) and vulval carcinoma (A431) cell lines. Systemic treatment of mice with all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid, IFN alpha or 1,25(OH)2D3 significantly decreased tumor cell-induced angiogenesis (TIA). In vitro pretreatment of T47D and A431 cells with these compounds also led to inhibition of their angiogenic capability when tested in the TIA assay. The inhibitory effects of retinoids could be counteracted by a selective antagonist of the nuclear retinoic acid receptor RAR alpha, suggesting a RAR alpha mediated mechanism of angiogenesis inhibition. The antiangiogenic effect of retinoids could be significantly enhanced by combination with IFN alpha or 1,25(OH)2D3. The results provide a further basis for the use of combinations of retinoids with IFN alpha or 1,25(OH)2D3 in the treatment of angiogenesis-dependent malignancies.
维甲酸与α-2a干扰素（IFNα）或1,25-二羟基维生素D3[1,25(OH)2D3]联合使用时，对携带致癌性人乳头瘤病毒（HPV）16型或18型DNA的肿瘤细胞系诱导的血管生成具有显著的协同抑制作用。本报告证明了这些化合物对非HPV转化细胞系（包括乳腺癌（T47D）和外阴癌（A431）细胞系）诱导的血管生成具有类似作用。用全反式维甲酸、13-顺式维甲酸、9-顺式维甲酸、IFNα或1,25(OH)2D3对小鼠进行全身治疗，可显著降低肿瘤细胞诱导的血管生成（TIA）。在TIA试验中检测时，用这些化合物对T47D和A431细胞进行体外预处理，也会导致其血管生成能力受到抑制。维甲酸的抑制作用可被核维甲酸受体RARα的选择性拮抗剂抵消，提示存在RARα介导的血管生成抑制机制。维甲酸与IFNα或1,25(OH)2D3联合使用时，其抗血管生成作用可显著增强。这些结果为维甲酸与IFNα或1,25(OH)2D3联合用于治疗血管生成依赖性恶性肿瘤提供了进一步依据。
