Novel bisphosphonates for prostate cancer therapy

用于前列腺癌治疗的新型双磷酸盐

基本信息

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
项目类别：
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

项目摘要

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）：该项目的总体目标是评估新型双膦酸盐缀合物治疗前列腺癌转移和肿瘤引起的骨痛的可行性。目前包括双膦酸盐在内的治疗主要是姑息性的。诸如生物利用度低、作为辅助治疗的临床影响很少或没有经过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引起了许多药物经济学问题，并且需要开发更有效的类似物。我们的专有药物设计采用维生素 B6 和核苷酸双膦酸盐缀合物来解决这些限制，并在功效和副作用方面提供潜在的改进。我们之前在转移性乳腺癌小鼠模型中的体内结果表明，用 MBC 化合物治疗后，肿瘤负荷和骨转移发生率降低。此外，在多发性骨髓瘤小鼠模型中，还证明了骨矿物质密度损失的恢复和存活率的提高。我们已经证明，MBC 双膦酸盐化合物在体外对成骨细胞具有独特且明显的作用。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磷酸盐支架在内的新型缀合物。这些化合物的抗增殖特性将在前列腺癌衍生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。最有效的结合物将在前列腺肿瘤引起的骨痛大鼠模型中通过一系列剂量水平进行测试。成功开发用于治疗前列腺癌引起的骨骼并发症的双磷酸盐缀合物将解决美国每年预计超过 200,000 例前列腺癌新病例目前未得到满足的医疗需求。我们的新型双膦酸盐缀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剂，可以防止骨转移及其相关骨骼并发症的出现。因此，这些疗法的开发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。