Oncology Department, Polyclinic Maymard, Bastia, France.
Anticancer Res. 2012 Jul;32(7):2769-81.
Platinum is well known for its anticancer activity, firstly used as cis-diaminedichloroplatinum (II) (CDDP), with a wide range of activity. Its main mechanism of action involves its binding to DNA. Gallium, another metal, has also demonstrated apoptotic effects on malignant cells, but through interaction with targets other than DNA, such as the membrane, cytoskeleton and proteasome, and on enzyme activities. An antitumor synergism between CDDP and both gallium and rhenium compounds has been demonstrated. For these reasons, we proposed to combine these three metals and to determine at which doses each compound could be administered without major toxicity. CDDP, tetrakis(1-octanol) tris(5-aminosalicylate)gallium(III), and a diseleno-ether rhenium(I) complex were used in this experimental study in breast cancer MCF-7 tumor-bearing mice. CDDP was administered intraperitoneally (i.p.) twice a week at the dose of 3 mg/kg. Tetrakis(1-octanol) tris(5-aminosalicylate) gallium (III) and rhenium(I) diseleno-ether complexes were administered orally, daily, five days a week for three weeks, at doses ranging from 20 to 100 mg/kg for the gallium compound and from 10 to 50 mg/kg for the rhenium compound. Doses of 10 mg/kg of rhenium(I) diseleno-ether, and 100 mg/kg of the salicylate gallium compound, in combination with CDDP induced a significant decrease of 50% of the tumor volume, by comparison with the control group. In contrast, the decrease of the tumor volume in mice treated by CDDP alone was less than 25%. Changes in the sequence of administration of the three metals will be discussed to improve the therapeutic index.
铂因其抗癌活性而广为人知，最初用作顺式二氨二氯铂（II）（CDDP），具有广泛的活性。其主要作用机制涉及与 DNA 的结合。另一种金属镓也已证明对恶性细胞具有凋亡作用，但通过与除 DNA 以外的靶标相互作用，如膜、细胞骨架和蛋白酶体以及酶活性。已经证明 CDDP 与镓和铼化合物之间具有抗肿瘤协同作用。基于这些原因，我们提出将这三种金属结合起来，并确定每种化合物在没有主要毒性的情况下可以给予多大剂量。在这项乳腺癌 MCF-7 肿瘤荷瘤小鼠的实验研究中，使用了 CDDP、四（1-辛醇）三（5-氨基水杨酸盐）镓（III）和二硒醚铼（I）配合物。CDDP 通过腹腔内（i.p.）给药，每周两次，剂量为 3mg/kg。四（1-辛醇）三（5-氨基水杨酸盐）镓（III）和铼（I）二硒醚配合物通过口服给药，每天一次，每周五天，连续三周，镓化合物的剂量范围为 20 至 100mg/kg，铼化合物的剂量范围为 10 至 50mg/kg。与对照组相比，10mg/kg 的铼（I）二硒醚和 100mg/kg 的水杨酸盐镓化合物与 CDDP 联合使用可使肿瘤体积减少 50%。相比之下，单独用 CDDP 治疗的小鼠肿瘤体积减少不到 25%。将三种金属的给药顺序进行改变以提高治疗指数。
