Summary Antibodies to type II collagen (CII) cause articular damage in collagen-induced arthritis (CIA) in mice as judged by passive transfer to naive animals of mAb to CII. We tested the hypothesis that mAb degrade cartilage structure by reacting with functionally important regions of the collagen molecule by examining the effects of an arthritogenic mAb to CII, CII-C1, on cultured bovine chondrocytes at high density, at days 7 and 14. The effects were compared of CII-C1, an isotype-matched control mAb, or medium alone, on chondrocyte proliferation and viability, cell morphology, matrix structure by light and electron microscopy, and matrix synthesis by metabolic labelling with 3 H-proline for collagen or 35 SO 4 for proteoglycans. Chondrocytes in culture remained viable, proliferated, and produced an extracellular matrix in which CII was the major collagen. The addition of CII-C1, but not a control mAb, increased the synthesis of CII and proteoglycan, and caused disorganization of the extracellular matrix and thin collagen fibrils ultrastructurally. Moreover, using a cell-free assay, CII-C1 inhibited the normal selfassembly of collagen fibrils from CII in solution. The finding that the mAb to CII, CII-C1 has striking degradative effects in vitro on cartilage synthesis suggests that antibodies to collagen perpetuate the chronic phase of CIA and that, in mice at least, such antibodies are an important component of pathogenesis.

Further studies are required to define the safety of the formulation of irinotecan with HA. While this study was not adequately powered to demonstrate survival differences, these phase II data indicated HA-Irinotecan to be a promising therapy demonstrating improved efficacy compared to irinotecan-alone.

Background: Preclinical data demonstrate that the polysaccharide hyaluronic acid (HA) acts as a macromolecular carrier for chemotherapeutic drugs. In these studies the formulation of HA and irinotecan reduced treatment-related toxicity and improved efficacy via the preferential delivery of irinotecan to the tumor and lymph nodes. This study was designed as a first-in-man investigation of the safety and pharmacokinetics of irinotecan when administered within the HA-Irinotecan formulation. Methods: 5-Fluorouracil refractory metastatic colorectal cancer patients were intravenously treated with HA-Irinotecan (300 mg/m² irinotecan with 1,000 mg/m² HA) on day 1 of a 21-day cycle. After safety was demonstrated, the irinotecan dose was increased to 350 mg/m² with maintenance of the HA at 1,000 mg/m².DELETEResults: Twelve patients were treated with HA-Irinotecan. Overall toxicity was low, with an 8 and 17% incidence of grade lll/lV diarrhea and neutropenia, respectively. No grade III/IV nausea or vomiting was observed. Seventeen percent of patients had a partial response and 50% experienced stable disease, indicating that the efficacy of the irinotecan was maintained. Median survival was 16.6 months, while median progression-free survival was 6.2 months. Conclusion: HA-Irinotecan containing standard doses of irinotecan can be safely administered to patients. Comparison to historical irinotecan data suggests HA-Irinotecan may have a greater margin of safety without compromising anticancer activity.

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