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

描述(由申请人提供)：化学大师国际公司(CMII)是一家小型化学制造公司，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。该公司自成立以来，已向较大的制药公司提供了许多新的和已知的化合物。在紫杉类化学领域，CMII为其生产SB-T-110131(由Ojima博士发现，后来编码为IDN5109)的Indena spa(意大利米兰)开发了多步汇聚商业流程。这还包括开发一种合成和引入异丝氨酸侧链的全新方法。基于这些成就和多步合成的经验，我们现在建议进行至少10g的DHA-SB-T-1214的合成(由Ojima博士发现并申请专利)，纯度为97%或更高。我们还建议Roswell Park癌症研究所的R Bernacki博士使用这种材料进行一系列测试，以确定这种多不饱和脂肪酸-紫杉醇类物质阻止或完全终止三种癌细胞株的生长的能力，即DLD-1(PGP+；人结肠)、H460-NSCLC(人肺)和BT-20(人乳房)，作为免疫受损小鼠的异种移植瘤。这些测试将针对一组相关的自由紫杉类药物物质进行，以比较其生物活性。尽管DHA-SB-T-1214的研究已经显示了对DLD-1异种移植瘤的真正特殊的活性(寿命延长到186天，基本上完全治愈)，但两种不同的药物样本注意到了一些毒性差异。因此，我们认为，这些实验应该对高度纯化的药物样本重复进行。对肺癌和乳腺癌细胞系的测试表明，试图将DHA-SB-T-1214的统治范围扩大到人类癌症的两种常见但异常难治的形式--肺癌和乳腺癌。所有的抗肿瘤试验都将在三个剂量水平上进行，第一个剂量水平确定最大耐受剂量(MTD)，其他两个分别为MTD的一半和十分之一。其目的是确定在临床环境下治疗上述类型癌症的合适剂量水平。考虑到过去对结肠癌细胞系DLD-1的研究结果，DHA-SB-T-1214的拟议开发看起来非常合理，其中抗肿瘤效果似乎比任何其他药物好一个数量级。7)项目说明： 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物质可以消除甚至部分抑制人类结肠癌的生长，因为这种特殊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-紫杉醇结合物，似乎能够选择性地穿透这些癌细胞，并绕过MDR装置，从而诱导细胞死亡。进一步开发这种物质作为治疗结肠癌和其他形式的癌症的可能方法，在一个这种多变量且基本上无法治疗的疾病似乎正在增加的社会中，几乎是非常重要的。

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.