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Bone marrow hypoplasia and pancytopenia are among the most undesirable sequelae of chemotherapy for the treatment of cancer. We recently showed that hyaluronan (HA) facilitates hematopoietic recovery in tumor-free animals receiving chemotherapeutic agents. However, following a chemotherapeutic regimen in tumor-bearing animals, it is possible that residual tumor cells might respond to systemic injections of HA. Thus, in this study, we investigated the effect of HA on the regrowth of residual tumor cells following chemotherapy. As a model, we used the HCT-8 human colon carcinoma cell line, which expresses the HA receptor CD44, binds exogenous HA, and is susceptible to a chemotherapy protocol containing irinotecan and 5-fluorouracil in a human/mouse xenograft model. HCT-8 cells were implanted in severe combined immunodeficient mice, followed by irinotecan/5-fluorouracil treatment. After three rounds of chemotherapy, residual tumors were allowed to regrow in the presence or absence of HA. The dynamics of tumor regrowth in the group treated with HA was slower compared with the control group. By week 5 after tumor implantation, the difference in the size of regrown tumors was statistically significant and correlated with lower proliferation and higher apoptosis in HA-treated tumors as compared with controls. This finding provides evidence that HA treatment does not stimulate but delays the growth of residual cancer cells, which is an important parameter in establishing whether the use of HA can enhance current chemotherapeutic strategies., (©2010 AACR.)