FGFs to Broadly Protect Chemotherapy-Induced Alopecia

FGF 可广泛保护化疗引起的脱发

• 批准号: 6935773
• 负责人: ZE LU
• 金额: $ 19.78万
• 依托单位: OPTIMUM THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-07 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935773
• 关键词: alopecia; antineoplastics; chemoprevention; dimethylsulfoxide; disease /disorder model; dosage; drug administration rate /duration; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; fibroblast growth factor; hair follicle; laboratory mouse; laboratory rat; liposomes; neoplasm /cancer chemotherapy; nonhuman therapy evaluation; pharmacokinetics; skin disorder chemotherapy; skin pharmacology; topical drug application

DESCRIPTION (provided by applicant): Chemotherapy-induced alopecia (CIA) is one of the most common and psychologically distressing side effects of cancer chemotherapy. CIA consists of hair loss, reduced hair growth, and structural abnormalities in the newly grown hair. Devastation due to CIA is often severe, and has prompted some patients to refuse chemotherapy. Concern for quality of life issue is gaining importance as the emphasis of cancer treatment is shifting from cure to long-term maintenance. Hence, effective treatment for CIA is needed and timely. No proven treatment for CIA is available. The several agents under development are designed to protect against a single drug or a single drug class and therefore have limited application against combination therapy using two or more drugs with different action mechanisms. The present application is to develop a treatment that can broadly protect against CIA by multiple drugs and drug classes. We have previously found that aFGF combined with bFGF (FGFs) induce up to 10-fold resistance in tumor cells against chemotherapy with multiple chemotherapeutic agents acting by diverse mechanisms. The resistance applies to both the anti-proliferative and apoptotic effects of drugs. Subcutaneous or topical application of FGFs in a neonatal rat model of alopecia reduced the hair loss induced by multiple anticancer drugs (paclitaxel, doxorubicin, cyclophosphamide, cytosine arabinoside), enhanced the subsequent hair growth, and reversed the chemotherapy-induced structural abnormalities in the hair follicles and hair shafts. This result is superior to the effect of published treatments for CIA. Additional preliminary results show that topically applied FGFs (dissolved in DMSO) were localized in hair follicles and the dermis layer and resulted in insignificant systemic absorption. We further found that our first generation liposomal formulation, when applied topically, was localized in hair follicles. Collectively, our preliminary results suggest that liposomal formulations of FGFs for topical administration can selectively protect against CIA without compromising the effectiveness of chemotherapy. The goal of this Phase I application is to develop topical FGF formulations for treating CIA.

描述（由申请人提供）：化疗诱导的脱发（CIA）是癌症化疗最常见和心理上最痛苦的副作用之一。CIA包括脱发，头发生长减少，新生长的头发结构异常。由于CIA的破坏往往是严重的，并促使一些患者拒绝化疗。随着癌症治疗的重点从治愈转向长期维持，对生活质量问题的关注越来越重要。因此，对CIA的有效治疗是必要和及时的。没有经过证实的治疗CIA是可用的。正在开发的几种药物被设计为针对单一药物或单一药物类别进行保护，因此对于使用具有不同作用机制的两种或更多种药物的联合治疗的应用有限。本申请旨在开发一种治疗方法，其可以通过多种药物和药物类别广泛地保护免受CIA。我们以前已经发现，aFGF与bFGF（FGF）的组合诱导肿瘤细胞对多种化疗药物通过不同的机制发挥作用的化疗高达10倍的阻力。耐药性适用于药物的抗增殖和凋亡作用。在新生大鼠脱发模型中皮下或局部应用FGF可减少多种抗癌药物（紫杉醇、多柔比星、环磷酰胺、阿糖胞苷）诱导的脱发，增强随后的毛发生长，并逆转化疗诱导的毛囊和毛干结构异常。该结果上级于已发表的CIA治疗效果。额外的初步结果显示，局部施用的FGF（溶解在DMSO中）定位于毛囊和真皮层中，并导致不显著的全身吸收。我们进一步发现，我们的第一代脂质体制剂在局部应用时定位于毛囊中。总的来说，我们的初步结果表明，局部给药的FGF脂质体制剂可以选择性地保护免受CIA，而不影响化疗的有效性。该I期申请的目标是开发用于治疗CIA的局部FGF制剂。