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）：该提案的目的是促进采用Metvan用于乳腺癌和脑肿瘤患者的创新治疗方案的设计。在25个（环戊烯基）气泡体（IV）和15种氧化剂（IV）化合物中，合成并评估了抗癌活性，BIS（4,7-二甲基-1,10-110-磷酸氨基氨基氨酸）硫酸磺胺硫酸硫酸硫磺烷（IV）[Metvan] [Metvan] [Metvan] [MetVAN]的抗抗逆点数是podition-proment Pertiver-nitiar perting perting perting perting apting vanting vanting vantering vanting vantering vanting vanting vantering vanting vanting vanting vanting vanting vantering。在纳摩尔和低微摩尔浓度下，Metvan诱导人白血病细胞，多发性骨髓瘤细胞以及源自乳腺癌，胶质母细胞瘤，卵巢瘤，前列腺和睾丸癌患者的实体瘤细胞的凋亡。它非常有效地针对抗二铂的大脑，卵巢癌和睾丸癌细胞系。 Metvan比标准化学治疗剂地塞米松和长春新碱在癌细胞中凋亡更有效。以浓度> 1MUM治疗乳腺癌或脑肿瘤细胞，与处理过的癌细胞群体的粘合剂，迁移和侵入性特性几乎完全丧失。 Metvan在小鼠中显示出有利的药代动力学，并不会在测试的剂量水平（12.5-100 mg/kg）下引起小鼠的急性或亚急性毒性。治疗性血浆浓度大于或等于5MUM，对人类癌细胞具有高度细胞毒性，可以在小鼠中迅速实现和维持，至少在I.P.后至少24小时。注射10 mg/kg元剂量的10 mg/kg无毒剂量。 Metvan表现出明显的抗肿瘤活性，延迟肿瘤进展并延长人类恶性胶质母细胞瘤和乳腺癌的严重合并免疫缺陷（SCID）小鼠异种移植模型。 Metvan的广谱抗癌活性以及有利的药效特征和缺乏毒性值得进一步发展这种新型的Oxovanadium化合物作为一种新的抗癌药。 Metvan作为抗癌剂的进一步发展将取决于相关动物模型中体内功效和药代动力学研究。现在，我们建议使用SCID小鼠模型来详细介绍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，这将产生对人类乳腺癌和脑肿瘤细胞挑战的SCID小鼠的最佳治疗指数。我们的具体目的是：（i）研究Metvan作为单一药物的体内抗癌活性，并与SCID小鼠异种乳腺癌和恶性胶质母细胞瘤的SCID小鼠异种移植模型中的标准化学治疗药物结合使用。 （ii）研究Metvan的体内药代动力学特征在SCID小鼠异种移植物的转移性人体乳腺癌和恶性胶质母细胞瘤模型中。从特定目标1-2中描述的这些研究中获得的知识有望促进使用Metvan用于转移性乳腺癌和脑肿瘤患者的创新治疗方案的设计。