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(申请人提供)：本项目的总体目标是评估新型双膦酸偶联物治疗前列腺癌转移和肿瘤引起的骨痛的可行性。目前的治疗方法包括双磷酸盐，主要是姑息治疗。生物利用度低，作为辅助治疗的临床影响很小或没有得到证实，以及骨骼并发症的适度减少等缺点，在双膦酸盐治疗中提出了许多药物经济学问题，并有必要开发更有效的类似物。我们的专利药物设计使用维生素B6和核苷酸双膦酸偶联物来解决这些限制，并在疗效和副作用方面提供潜在的改善。我们先前在转移性乳腺癌小鼠模型上的体内结果显示，使用MBC化合物治疗后，肿瘤负担和骨转移发生率降低。此外，在多发性骨髓瘤的小鼠模型中，还证明了骨密度丢失的恢复和存活率的提高。我们已经证明了MBC双膦酸盐化合物对体外培养的成骨细胞具有独特而独特的作用。在这项拟议的工作中，我们的专利化学将用于开发包括第三代双膦酸类支架在内的新型共轭化合物。这些化合物的抗增殖特性将在前列腺癌来源的细胞系和人类成骨细胞系中进行测试，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一系列剂量水平在前列腺肿瘤引起的骨痛的大鼠模型中进行测试。成功开发用于治疗前列腺癌引起的骨骼并发症的双膦酸偶联物，将满足目前未得到满足的医疗需求，预计美国每年新增前列腺癌病例20万例。我们的新型双膦酸偶联物不仅可以用于治疗骨转移瘤及其相关疼痛，而且可能被证明是预防骨转移瘤及其相关骨骼并发症的有效预防药物。因此，这些疗法的发展不仅可以改善前列腺癌患者的生活质量，还可以延长他们的生命。