Novel bisphosphonates for prostate cancer therapy

用于前列腺癌治疗的新型双磷酸盐

• 批准号: 7217601
• 负责人: Alexander Karpeisky
• 金额: $ 10万
• 依托单位: MBC PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-07 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217601
• 关键词: Address; Adjuvant Therapy; Adverse effects; Affinity; Appearance; Ara-C; Architecture; Biological Assay; Biological Availability; Bone Density; Bone Diseases; Bone Pain; Cancer Patient; Cause of Death; Cell Line; Cells; Cessation of life; Chemistry; Clinical; Development; Diagnostic radiologic examination; Disadvantaged; Dose; Drug Design; Fluorouracil; Generations; Goals; Human; Hydroxyapatites; Hyperalgesia; Hypercalcemia; In Vitro; Incidence; Laboratories; Lead; Lesion; Life; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Measures; Mechanics; Medical; Metastatic Neoplasm to the Bone; Microcomputers; Modality; Modeling; Morbidity - disease rate; Multiple Myeloma; Mus; Neoplasm Metastasis; Nerve compression syndrome; Nucleosides; Nucleotides; Numbers; Osteoblasts; Osteocalcin; Osteoclasts; PC3 cell line; Pain; Pain Measurement; Pathological fracture; Patients; Pharmaceutical Economics; Phase I Clinical Trials; Physiologic calcification; Powder dose form; Preparation; Procedures; Property; Prostate Cancer therapy; Prostate carcinoma; Prostatic; Protocols documentation; Publishing; Quality of life; Range; Rattus; Sampling; Serum; Skeletal system; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Staining method; Stains; Testing; Therapeutic; Tumor Burden; Vitamin B6; Work; allodynia; analog; base; bisphosphonate; bone; cancer diagnosis; chemical property; concept; day; fetal; improved; in vivo; in vivo Model; male; malignant breast neoplasm; mecarzole; men; mineralization; mouse model; novel; prevent; prophylactic; research study; restoration; scaffold; tartrate-resistant acid phosphatase; tibia; tomography; tumor; tumor growth

DESCRIPTION (provided by applicant): The overall aim of this project is to evaluate the feasibility of novel bisphosphonate conjugates as treatment for prostate cancer metastasis and tumor-induced bone pain. Current treatments including bisphosphonates are mainly palliative. Disadvantages such as low bioavailability, little or no proven clinical impact as adjuvant therapy, and moderate reduction of skeletal complications raise numerous pharmacoeconomic issues in bisphosphonate treatment and necessitate the development of more efficacious analogs. Our proprietary drug designs employ vitamin B6- and, nucleotide-bisphosphonate conjugates to address these limitations and offer potential improvements in efficacy and side-effect profiles. Our prior in vivo results in mouse models of metastatic breast cancer showed decreased tumor burden and incidence of bone metastases upon treatment with MBC compounds. In addition, restoration of bone mineral density loss and increased survival in a mouse model of multiple myeloma was demonstrated. We have shown that MBC bisphosphonate compounds have unique and distinct effects on osteoblasts in vitro. In this proposed work, our proprietary chemistry will be used to develop novel conjugates that include third generation bisphophonate scaffolds. The antiproliferative properties of these compounds will be tested in prostate cancer derived and human osteoblast cell lines; and their effects on osteoblast cell mineralization will be assessed. The most potent conjugates will be tested through a range of dose levels in a rat model of prostatic tumor induced bone pain. Successful development of bisphosphontate conjugates for the treatment of prostate cancer induced skeletal complications would address the currently unmet medical needs of the >200,000 new cases of prostate cancer anticipated every year in the US. Our novel bisphosphonate conjugates may not only be used as a therapy for the treatment of bone metastatises and its related pain, but may prove to be an effective prophylactic that prevents the appearance of bone metastases and their related skeletal complications. Thus, the development of these therapeutics may not only improve the quality of life for prostate cancer patients but may also prolong their lives.

描述（由申请人提供）：该项目的总体目的是评估新型双膦酸盐偶联物作为前列腺癌转移和肿瘤诱发的骨痛的可行性。包括双膦酸盐在内的当前治疗主要是姑息治疗。诸如低生物利用度，辅助治疗（辅助治疗）的临床影响很少或没有证实的缺点以及骨骼并发症的适度减少引起了双膦酸盐治疗中的许多药物经济问题，因此需要发展更有效的类似物。我们的专有药物设计采用了维生素B6-和核苷酸三膦酸盐偶联物来解决这些局限性，并提供了疗效和副作用谱的潜在改善。我们先前的体内导致转移性乳腺癌的小鼠模型显示，用MBC化合物治疗后肿瘤负担下降和骨转移的发生率。另外，在多发性骨髓瘤的小鼠模型中，骨矿物质密度损失的恢复和增加的生存率已被证明。我们已经表明，MBC双膦酸盐化合物对体外成骨细胞具有独特而独特的影响。在这项拟议的工作中，我们的专有化学将用于开发包括第三代双载脚架在内的新型结合物。这些化合物的抗增殖特性将在衍生的前列腺癌和成骨细胞细胞系中进行测试。并将评估它们对成骨细胞矿化的影响。最有效的结合物将通过前列腺肿瘤诱导的骨痛的大鼠模型中的一系列剂量水平进行测试。双膦酸盐偶联物用于治疗前列腺癌引起的骨骼并发症的成功开发将解决美国目前未满足的医疗需求，即每年预计在美国预计的200,000例新的前列腺癌病例。我们新型的双膦酸盐结合物不仅可以用作治疗骨转移及其相关疼痛的疗法，而且可能被证明是一种有效的预防性，可防止骨转移及其相关骨骼并发症的出现。因此，这些治疗剂的发展不仅可以改善前列腺癌患者的生活质量，而且可能会延长其寿命。