METVAN: A Novel Anticancer Agent

描述(由申请人提供)：本提案的目标是促进使用METVAN治疗乳腺癌和脑瘤患者的创新治疗方案的设计。在合成并评价其抗癌活性的25个双(环戊二烯)钒(IV)和15个氧钒(IV)化合物中，双(4，7-二甲基-1，10-菲咯啉)磺基氧钒(IV)[METVAN]被认为是最有希望的具有诱导细胞凋亡活性的多靶点抗癌钒配合物。在纳摩尔和低微摩尔浓度下，METVAN诱导人类白血病细胞、多发性骨髓瘤细胞以及乳腺癌、胶质母细胞瘤、卵巢癌、前列腺癌和睾丸癌患者的实体瘤细胞凋亡。它对对顺铂耐药的脑、卵巢和睾丸癌细胞株非常有效。METVAN在诱导癌细胞凋亡方面比标准化疗药物地塞米松和长春新碱有效得多。用浓度为&gt；1muM的METVAN治疗乳腺癌或脑瘤细胞几乎完全丧失了被治疗的癌细胞群体的粘附性、迁移性和侵袭性。METVAN在小鼠体内显示良好的药代动力学，在所测试的剂量水平(12.5-100 mg/kg)不会对小鼠造成急性或亚急性毒性。对人类癌细胞具有高度细胞毒性的治疗性血浆浓度大于或等于5微米，在小鼠体内可以迅速达到并维持至少24小时。单次推注10 mg/kg无毒剂量的甲氨蝶呤。在人恶性胶质母细胞瘤和乳腺癌的严重联合免疫缺陷(SCID)小鼠移植模型中，METVAN显示出显著的抗肿瘤活性，延缓肿瘤进展和延长生存时间。METVAN的广谱抗癌活性、良好的药效学特性和无毒性，为进一步开发这一新型氧钒化合物作为一种新型抗癌药物提供了依据。METVAN作为抗癌药物的进一步发展将取决于相关动物模型的体内疗效和药代动力学研究。我们现在建议使用SCID小鼠模型进行详细的体内抗癌活性和药代动力学分析，以确定METVAN的全身暴露水平，这将在挑战人乳腺癌和脑肿瘤细胞的SCID小鼠中产生最佳治疗指数。我们的具体目标是：(1)研究METVAN作为单一药物和联合标准化疗药物对人转移性乳腺癌和恶性胶质母细胞瘤SCID小鼠异种移植瘤的体内抗癌活性。(2)研究METVAN在人转移性乳腺癌和恶性胶质母细胞瘤SCID小鼠移植瘤模型中的体内药代动力学特征。从具体目标1-2中描述的这些研究中获得的知识有望促进使用METVAN治疗转移性乳腺癌和脑瘤患者的创新治疗方案的设计。

DESCRIPTION (provided by applicant): The goal of this proposal is to facilitate the design of innovative treatment regimens employing METVAN for breast cancer and brain tumor patients. Among the 25 bis(cyclopentadienyl)vanadium(IV) and 15 oxovanadium(IV) compounds synthesized and evaluated for anticancer activity, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV) [METVAN] was identified as the most promising multitargeted anticancer vanadium complex with apoptosis-inducing activity. At nanomolar and low micromolar concentrations, METVAN induces apoptosis in human leukemia cells, multiple myeloma cells, and solid tumor cells derived from breast cancer, glioblastoma, ovarian, prostate, and testicular cancer patients. It is highly effective against cisplatin-resistant brain, ovarian and testicular cancer cell lines. METVAN is much more effective than standard chemotherapeutic agents dexamethasone and vincristine in inducing apoptosis in cancer cells. Treatment of breast cancer or brain tumor cells with METVAN at concentrations >1muM is associated with a nearly complete loss of the adhesive, migratory, and invasive properties of the treated cancer cell populations. METVAN shows favorable pharmacokinetics in mice and does not cause acute or subacute toxicity in mice at dose levels tested (12.5 - 100 mg/kg). Therapeutic plasma concentrations greater than or equal to 5muM, which are highly cytotoxic against human cancer cells, can be rapidly achieved and maintained in mice for at least 24 h after i.p. bolus injection of a single 10 mg/kg nontoxic dose of METVAN. METVAN exhibits significant antitumor activity, delays tumor progression and prolongs survival time in severe combined immunodeficiency (SCID) mouse xenograft models of human malignant glioblastoma and breast cancer. The broad-spectrum anticancer activity of METVAN together with favorable pharmacodynamic features and lack of toxicity warrants further development of this novel oxovanadium compound as a new anticancer drug. The further development of METVAN as an anticancer agent will depend on in vivo efficacy and pharmacokinetic studies in relevant animal models. We are now proposing to use the SCID mouse model for detailed in vivo anticancer activity and pharmacokinetic analysis to determine the systemic exposure levels of METVAN, which would yield the best therapeutic index in SCID mice challenged with human breast cancer and brain tumor cells. Our specific aims are: (i) To study the in vivo anticancer activity of METVAN as a single agent and in combination with standard chemotherapeutic drugs in SCID mouse xenograft models of metastatic human breast cancer and malignant glioblastoma. (ii) To study the in vivo pharmacokinetic features of METVAN in SCID mouse xenograft models of metastatic human breast cancer and malignant glioblastoma. The knowledge gained from these studies described under Specific Aims 1-2 is expected to facilitate the design of innovative treatment regimens employing METVAN for metastatic breast cancer and brain tumor patients.