Peclinical Studies on a Polyunsaturated Fatty acid-Taxoid Conjugate for IND Fili

描述（由申请人提供）：Chem-Master International Inc. CMII是一家小型化学品制造公司，成立于1994年，旨在满足工业和学术团体的需求，这些团体无法轻松获得一系列生物活性物质或其合成中间体。自成立以来，该公司已向大型制药公司提供了许多新的和已知的化合物。在紫杉烷化学领域，CMII开发了由Indena SpA（米兰，意大利）生产SB-T-110131（由Ojima博士发现，后来编码为IDN 5109）的多步聚合商业工艺。这也包括开发一种全新的方法来合成和引入异丝氨酸侧链。基于这些成就和多步合成的经验，我们现在建议合成至少10 g纯度为97%或更高的DHA-SB-T-1214（由Ojima博士发现并获得专利）。我们还建议Roswell Park癌症研究所的R Bernacki博士在一系列试验中使用这种材料，以确定这种PUFA-紫杉烷物质阻止或完全终止三种癌细胞系生长的能力，即DLD-1（Pgp+;人结肠），H460-NSCLC（人肺）和BT-20（人乳腺），这些细胞系在免疫功能低下的小鼠中作为异种移植物开发。将针对一组相关游离紫杉烷原料药进行这些试验，以比较生物活性。尽管DHA-SB-T-1214的研究已经显示出对DLD-1异种移植物的真正特殊活性（寿命延长至186天，基本上完全治愈），但在两种不同的药物样品中注意到一些毒性差异。因此，我们认为这些实验应该用高度纯化的药物样品重复进行。对肺癌和乳腺癌细胞系的测试代表了将DHA-SB-T-1214的自治领扩展到两种常见但独特难治的人类癌症形式-肺癌和乳腺癌的尝试。所有抗肿瘤试验将在三个剂量水平下进行，第一个剂量水平用于确定最大耐受剂量（MTD），其他剂量水平分别为MTD的一半和十分之一。目的是确定在临床环境中治疗上述类型癌症的适当剂量水平。鉴于结肠癌细胞系DLD-1的既往结果，DHA-SB-T- 1214的拟定开发看起来是高度合理的，其中抗肿瘤作用似乎比任何其他药物都好一个数量级。7）项目叙述： 拟议的项目与人类健康密切相关。目前还没有真正有效的药物可以消除或甚至部分抑制人结肠癌的生长，因为这种特定形式的癌症过度表达MDR表型。值得注意的是，DHA-SB-T-1214，一种多不饱和脂肪酸-紫杉烷缀合物，似乎能够选择性地穿透这些癌细胞并绕过MDR装置，然后诱导细胞死亡。这种物质作为结肠癌和其他形式癌症的可能治疗方法的进一步发展，在一个许多形式的这种多变量和基本上无法治疗的疾病似乎正在增加的社会中几乎没有更相关的了。

DESCRIPTION (provided by applicant): Chem-Master International Inc. (CMII) is a small chemical manufacturing company that was established in 1994 to serve the needs of both industrial and academic groups, who did not have easy access to a range of biologically-active substances or their synthetic intermediates. The Company, since its origin, has provided many new and known compounds to larger pharmaceutical companies. In the realm of taxoid chemistry, CMII developed the multi-step convergent commercial process for its production by Indena SpA (Milan, Italy) of SB-T-110131 (discovered by Dr. Ojima and later coded as IDN5109). This also included the development of an entirely new method for the synthesis and introduction of the iso-serine side chain. Based on these accomplishments and experience in multi-step synthesis, we now propose to undertake the synthesis of at least 10g of DHA-SB-T-1214 (discovered and patented by Dr. Ojima) with 97% or better purity. We also propose that this material then be used by Dr. R Bernacki of the Roswell Park Cancer Institute in a series of assays to determine the ability of this PUFA-taxoid substance to arrest or completely terminate the growth of three cancer cell lines, namely DLD-1 (Pgp+; human colon), H460-NSCLC (human lung) and BT-20 (human breast) developed as xenografts in immuno-compromised mice. These tests will be conducted against a panel of related free taxoid drug substances, for comparisons of biologic activity. Although studies with DHA-SB-T-1214 have already shown truly exceptional activity against the DLD-1 xenograft (life extension to 186 days essentially complete cure) some toxicity differences were noted with two different samples of the drug. Thus we believe that these experiments should be repeated with a drug sample that has been highly purified. Tests on the lung and breast cancer cell lines represent an attempt to extend the dominion of DHA-SB-T-1214 to two common but singularly refractory forms of human cancer-- lung and breast. All of the anti-tumor assays will be conducted at three dose levels, the first to determine the maximum tolerated dose (MTD) and the others at one half and one tenth respectively of the MTD. The objective is to define, what dose levels would be appropriate to treat the above types of cancer in a clinical setting. The proposed development of DHA-SB-T- 1214 looks highly justified in view of the past results with the colon cancer cell line DLD-1 where the anti-tumor effects appear to be one order of magnitude better than has been seen with any other drug.7) Project Narrative: The proposed project is of great relevance to human health. Currently there are no really effective drug substances that can abolish or even partially inhibit the growth of human colon cancer because this particular form of cancer over-expresses the MDR phenotype. Remarkably DHA-SB-T-1214, a polyunsaturated fatty acid -taxoid conjugate, seems to be able to penetrate these cancer cells selectively and to by-pass the MDR apparatus, thereafter inducing cell death. The further development of this substance as a possible treatment for both colon and other forms of cancer could scarcely be more relevant in a society where many forms of this multi-variate and largely untreatable disease, seem to be increasing.