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. ? ? ?
