METVAN: A Novel Anticancer Agent

METVAN：一种新型抗癌剂

• 批准号: 6689095
• 负责人: OSMOND J D'CRUZ
• 金额: $ 10万
• 依托单位: PARADIGM PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6689095
• 关键词: SCID mouse; antineoplastics; astrocytoma; atomic absorption spectrometry; breast neoplasms; carmustine; cisplatin; combination chemotherapy; drug screening /evaluation; histopathology; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; organometallic compounds; paclitaxel; pharmacokinetics; vanadium; xenotransplantation

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.

描述（由申请人提供）：该提案的目标是促进采用 METVAN 治疗乳腺癌和脑肿瘤患者的创新治疗方案的设计。在合成并评估抗癌活性的 25 种双（环戊二烯基）钒（IV）和 15 种氧钒（IV）化合物中，双（4,7-二甲基-1,10-菲咯啉）磺基氧钒（IV）[METVAN]被确定为最有效的化合物。最有前途的多靶点抗癌钒络合物，具有细胞凋亡诱导活性。在纳摩尔和低微摩尔浓度下，METVAN 可诱导人白血病细胞、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。它对顺铂耐药的脑、卵巢和睾丸癌细胞系非常有效。 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更有效。使用浓度 >1μM 的 METVAN 治疗乳腺癌或脑肿瘤细胞时，所治疗的癌细胞群的粘附、迁移和侵袭特性几乎完全丧失。 METVAN 在小鼠中显示出良好的药代动力学，并且在测试剂量水平（12.5 - 100 mg/kg）下不会对小鼠产生急性或亚急性毒性。小鼠体内可快速达到大于或等于 5μM 的治疗血浆浓度，该浓度对人类癌细胞具有高度细胞毒性，并在腹腔注射后维持至少 24 小时。单次推注 10 mg/kg 无毒剂量的 METVAN。 METVAN 在人类恶性胶质母细胞瘤和乳腺癌的严重联合免疫缺陷 (SCID) 小鼠异种移植模型中表现出显着的抗肿瘤活性，延缓肿瘤进展并延长生存时间。 METVAN 的广谱抗癌活性以及良好的药效学特征和无毒性保证了这种新型氧钒化合物作为新抗癌药物的进一步开发。 METVAN 作为抗癌药物的进一步开发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，这将在接受人类乳腺癌和脑肿瘤细胞攻击的 SCID 小鼠中产生最佳治疗指数。我们的具体目标是： (i) 在转移性乳腺癌和恶性胶质母细胞瘤的 SCID 小鼠异种移植模型中研究 METVAN 作为单药以及与标准化疗药物联合使用的体内抗癌活性。 (ii) 研究 METVAN 在转移性人乳腺癌和恶性胶质母细胞瘤 SCID 小鼠异种移植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预计将有助于设计采用 METVAN 治疗转移性乳腺癌和脑肿瘤患者的创新治疗方案。