Use of hyaluronan for treatment of chemotherapy sequelae

描述（由申请人提供）：在治疗癌症的化疗和放疗中，最不受欢迎的后遗症是骨髓发育不全和全血细胞减少。这些可进一步导致免疫缺陷，出血和缺氧显著影响癌症患者的发病率。调节造血干细胞（HSC）增殖的生长因子的发现导致了缩短化疗后中性粒细胞减少期的药物的开发。然而，这些药物通过细胞谱系竞争加重血小板减少症，如果与重复化疗周期一起使用，可能导致干细胞衰竭，从而恶化治疗结果。我们最近证明透明质酸（HA）刺激接受化疗药物的动物骨髓造血。这项技术是基于透明质酸靶向支持造血的调节利基的能力。因此，我们认为透明质酸是治疗癌症患者化疗后后遗症的候选药物。在本应用的第一个特定目的中，我们建议研究HA在荷瘤动物中的造血支持作用。我们将测试透明质酸对NOD/SCID结肠癌小鼠化疗后造血恢复动力学的影响。荷瘤小鼠和无瘤小鼠分别用伊立替康/5-氟尿嘧啶治疗，然后静脉输注透明质酸。将在对照组和ha治疗小鼠中评估外周血中成熟细胞（白细胞、血小板和红细胞）的数量以及骨髓中多能造血干细胞和固定淋巴细胞和髓细胞祖细胞的数量。这些研究将证明肿瘤细胞的存在是否会干扰血凝素的造血支持作用。在化疗后，一些残留的肿瘤细胞可能对全身注射HA有反应。因此，在第二个Specific Aim中，我们将在NOD/SCID小鼠中测试HA对人结肠癌生长的影响。伊立替康/5-氟尿嘧啶治疗的肿瘤在没有HA的情况下允许再生长。将监测高分子量透明质酸组和低分子量透明质酸组的肿瘤生长动态，并与对照组进行比较。该实验将为HA对残留癌细胞的抑制或刺激作用提供证据，并将成为确定HA是否可以增强当前化疗策略的重要参数。在这个i期申请中提出的研究将解决在癌症患者中使用透明质酸的重要安全性和有效性问题，并将为开发透明质酸作为一种新型药物来增强当前的癌症治疗铺平道路。

DESCRIPTION (provided by applicant): Among the most undesirable sequelae of chemo- and radiotherapies for the treatment of cancer are bone marrow hypoplasia and pancytopenia. These can further lead to immunodeficiency, bleeding and hypoxia significantly impacting the morbidity of cancer patients. The discovery of growth factors that regulate hematopoietic stem cells (HSC) proliferation led to the development of drugs that shorten the period of neutropenia post-chemotherapy. However, these drugs aggravate thrombocytopenia through cell lineage competition, and if used with repeated cycles of chemotherapy, can result in stem cell exhaustion, thus worsening treatment outcomes. We recently demonstrated that hyaluronan (HA) stimulates bone marrow hematopoiesis in animals receiving chemotherapeutic agents. This technology is based on the ability of HA to target a regulatory niche that supports hematopoiesis. We propose therefore that HA is a drug candidate for the management of post-chemotherapy sequelae in cancer patients. In the first Specific Aim of this application we propose to investigate the hematopoiesis-supportive effect of HA in tumor-bearing animals. We will test the effect of HA on the dynamics of post-chemotherapy hematopoietic recovery in NOD/SCID mice bearing human colon carcinoma. Tumor-bearing mice and tumor-free mice will be treated with irinotecan/5- fluorouracil followed by intravenous infusion of HA. The number of mature cells (leukocytes, platelets and erythrocytes) in peripheral blood as well as the number of multipotent HSC and committed lymphoid and myeloid progenitors in the bone marrow will be evaluated in control and HA-treated mice. These studies will demonstrate whether the presence of tumor cells might interfere with the hematopoiesis-supportive effects of HA. Following a chemotherapeutic regime, it is possible that some remaining tumor cells might respond to systemic injections of HA. Therefore, in the second Specific Aim, we will test the effects of HA on human colon carcinoma growth in NOD/SCID mice. The irinotecan/5-fluorouracil treated tumors will be allowed to re- grow in the presence of absence of HA. The dynamics of tumor growth in the groups treated with high molecular weight HA and low molecular weight HA will be monitored and compared to control. This experiment will provide evidence relating to the effects of HA on residual cancer cells, be it inhibitory or stimulatory, and will be an important parameter in establishing whether HA can enhance current chemotherapeutic strategies. The studies proposed in this Phase 1 application will address important safety and efficacy concerns about the use of HA in cancer patients, and will pave the way for developing HA as a novel drug to enhance current cancer therapies. Relevance. Hyaluronan has a great potential to be developed as a drug to stimulate the recovery of peripheral blood cells in post-chemotherapy patients. The use of hyaluronan can be potentially more beneficial for the cancer patients compared to the existing cytokine- based drugs. Hyaluronan is not toxic and not immunogenic. Hyaluronan is inexpensive to manufacture and therefore can be easily available for the underserved population of patients. The proposed studies will address the question of whether HA is safe and efficacious in tumor bearing animals. If successful, these data will provide substantial rationale supporting the use of HA in cancer patients undergoing chemotherapy.