Teicher B A, Sotomayor E A, Huang Z D, Ara G, Holden S, Khandekar V, Chen Y N
Dana-Farber Cancer Institute, Boston, MA 02115.
Cancer Chemother Pharmacol. 1993;33(3):229-38. doi: 10.1007/BF00686221.
Tetrahydrocortisol, beta-cyclodextrin tetradecasulfate, and minocycline used alone or in combination are not very cytotoxic toward EMT-6 mouse mammary tumor cells growing in monolayer. Tetrahydrocortisol (100 microM, 24 h) and beta-cyclodextrin tetradecasulfate (100 microM, 24 h) protected EMT-6 cells from the cytotoxicity of CDDP, melphalan, 4-hydroperoxycyclophosphamide, BCNU, and X-rays under various conditions of oxygenation and pH. Minocycline (100 microM, 24 h) either had no effect upon or was additive with the antitumor alkylating agents or X-rays in cytotoxic activity toward the EMT-6 cells in culture. The combination of the three modulators either had no effect upon or was to a small degree protective against the cytotoxicity of the antitumor alkylating agents or X-rays. The Lewis lung carcinoma was chosen for primary tumor growth-delay studies and tumor lung-metastases studied. Tetrahydrocortisol and beta-cyclodextrin tetradecasulfate were given in a 1:1 molar ratio by continuous infusion over 14 days, and minocycline was given i.p. over 14 days, from day 4 to day 18 post tumor implantation. The combination of tetrahydrocortisol/beta-cyclodextrin tetradecasulfate diminished the tumor growth delay induced by CDDP and melphalan and produced modest increases in the tumor growth delay produced by cyclophosphamide and radiation. Minocycline co-treatment increased the tumor growth delay produced by CDDP, melphalan, radiation, bleomycin, and, especially cyclophosphamide, where 4 of 12 animals receiving minocycline (14 x 5 mg/kg, days 4-18) and cyclophosphamide (3 x 150 mg/kg, days 7, 9, 11) were long-term survivors. The 3 modulators given in combination produced further increases in tumor growth delay with all of the cytotoxic therapies, and 5 of 12 of the animals treated with the 3-modulator combination and cyclophosphamide were long-term survivors. Although neither tetrahydrocortisol/beta-cyclodextrin tetradecasulfate, minocycline, nor the three modulator combination impacted the number of lung metastases, there was a decrease in the number of large lung metastases. Treatment with the cytotoxic therapies alone reduced the number of lung metastases. Addition of the modulators to treatment with the cytotoxic therapies resulted in a further reduction in the number of lung metastases. These results indicate that agents that inhibit the breakdown of the extracellular matrix can be useful additions to the treatment of solid tumors.
单独使用或联合使用的四氢皮质醇、β-环糊精十四硫酸盐和米诺环素对单层生长的EMT-6小鼠乳腺肿瘤细胞的细胞毒性不大。在不同的氧合和pH条件下，四氢皮质醇（100微摩尔，24小时）和β-环糊精十四硫酸盐（100微摩尔，24小时）可保护EMT-6细胞免受顺铂、美法仑、4-氢过氧环磷酰胺、卡莫司汀和X射线的细胞毒性。米诺环素（100微摩尔，24小时）对培养中的EMT-6细胞的细胞毒性活性要么对抗肿瘤烷化剂或X射线没有影响，要么具有相加作用。三种调节剂的组合要么对抗肿瘤烷化剂或X射线的细胞毒性没有影响，要么在一定程度上具有保护作用。选择Lewis肺癌进行原发性肿瘤生长延迟研究和肿瘤肺转移研究。四氢皮质醇和β-环糊精十四硫酸盐以1:1的摩尔比连续输注14天，米诺环素在肿瘤植入后第4天至第18天腹腔注射14天。四氢皮质醇/β-环糊精十四硫酸盐的组合减少了顺铂和美法仑诱导的肿瘤生长延迟，并适度增加了环磷酰胺和辐射诱导的肿瘤生长延迟。米诺环素联合治疗增加了顺铂、美法仑、辐射、博来霉素，尤其是环磷酰胺诱导的肿瘤生长延迟，接受米诺环素（14×5毫克/千克，第4 - 18天）和环磷酰胺（3×150毫克/千克，第7、9、11天）治疗的12只动物中有4只长期存活。三种调节剂联合使用在所有细胞毒性治疗中进一步增加了肿瘤生长延迟，接受三种调节剂联合治疗和环磷酰胺治疗的12只动物中有5只长期存活。虽然四氢皮质醇/β-环糊精十四硫酸盐、米诺环素或三种调节剂的组合都不影响肺转移的数量，但大的肺转移数量有所减少。单独使用细胞毒性疗法可减少肺转移的数量。在细胞毒性疗法中添加调节剂可进一步减少肺转移的数量。这些结果表明，抑制细胞外基质分解的药物可作为实体瘤治疗的有益补充。
