New Triterpenoids for Cancer Chemoprevention and Therapy

描述（由申请人提供）：整个项目基于这样的假设，即我们可以设计和开发新的合成三萜类化合物，这些化合物最终将在临床上用于癌症的化学预防和治疗。该项目有6个具体目标，涵盖了临床前研究的整个范围，从新药设计，阐明其生物活性和分子作用机制，研究其药代动力学，最后，在被认为与实际人类疾病相关的致癌动物模型中测试预防癌症的有效性。我们的具体目标如下：（1）继续合成新的三萜类化合物，我们的优先事项由随后的具体目标中描述的体外和体内测试系统中获得的结果确定。这些研究将与达特茅斯学院化学系合作完成。(2)在一系列与癌症化学预防相关的细胞培养试验中，继续检测来自特定目标1的新三萜类化合物的生物活性。这样的测定将测量抗增殖和凋亡活性、肿瘤细胞分化的诱导和抗炎活性。(3)在细胞生物学和分子生物学试验中评价Specific Aim 1中新三萜类化合物的分子作用机制。结合这些研究，我们将试图确定介导达特茅斯合成三萜类化合物的抗增殖、凋亡、抗炎和分化作用的最接近的分子靶点。(4)评价新三萜类化合物诱导人类致癌相关细胞凋亡的能力，特别强调诱导永生化人类乳腺上皮细胞（非肿瘤性和肿瘤性）凋亡。(5)在临床前研究中评估有前途的新三萜类化合物的药代动力学，以优化最终可能用于预防男性和女性癌症的药物选择。作为药代动力学的辅助，我们还将在大鼠和小鼠中进行一些短期毒性的初步试验。(6)在适当的动物模型中测试有前途的新三萜类化合物，用于癌症的化学预防，特别强调预防乳腺癌和结肠癌。以前在该资助下合成的三萜类化合物已经在考虑用于治疗白血病的临床用途。从历史上看，许多化学预防剂已进入临床使用的癌症预防，首先被证明是积极的治疗方案，我们打算继续追求这种串扰之间的治疗和预防方法的癌症问题的结果提出的新的研究。

DESCRIPTION (provided by applicant): This entire project is based on the hypothesis that we can design and develop new synthetic triterpenoids that would eventually be clinically useful for chemoprevention and treatment of cancer. The project is articulated in 6 Specific Aims that cover the entire range of preclinical studies, all the way from design of new drugs, elucidation of their biological activity and molecular mechanism of action, study of their pharmacokinetics, and finally, testing of efficacy for prevention of cancer in animal models of carcinogenesis that are considered relevant to actual human disease. Our Specific Aims are as follows: (1) To continue to synthesize new triterpenoids, with our priorities determined by results obtained in the in vitro and in vivo test systems described in the subsequent Specific Aims. These studies will be done in collaboration with the Department of Chemistry at Dartmouth College. (2) To continue to test the new triterpenoids from Specific Aim 1 for their biological activity on a series of cell culture assays that are relevant to chemoprevention of cancer. Such assays will measure anti-proliferative and apoptotic activity, induction of differentiation in tumor cells, and anti-inflammatory activity. (3) To evaluate the molecular mechanism of action, in cell biology and molecular biology assays, of the new triterpenoids from Specific Aim 1. In conjunction with these studies, we will attempt to identify the proximate molecular target(s) that mediates the anti-proliferative, apoptotic, anti-inflammatory, and differentiating actions of the synthetic triterpenoids made at Dartmouth. (4) To evaluate the ability of new triterpenoids to induce apoptosis in cells that are relevant to human carcinogenesis, with special emphasis on induction of apoptosis in immortalized human breast epithelium, both non-neoplastic and neoplastic. (5) To evaluate the pharmacokinetics of promising new triterpenoids, in preclinical studies, to optimize choice of agents that might eventually be used for preventing cancer in men and women. As an adjunct to the pharmacokinetics, we will also undertake some preliminary assays of short-term toxicity in rats and mice. (6) To test promising new triterpenoids in appropriate animal models for chemoprevention of cancer, with special emphasis on prevention of breast and colon cancer. Triterpenoids previously synthesized with support from this grant are already under consideration for clinical use in treatment of leukemia. Historically, many chemopreventive agents have entered clinical use for cancer prevention by first being shown to be active in treatment protocols, and we intend to continue to pursue this cross-talk between therapeutic and preventive approaches to the cancer problem with the results of the proposed new studies.