The effect of hyaluronic acid on the activity of intra-tumoral and intestinal β-Glucuronidases - a potential mechanism for increasing the therapeutic index of Irinotecan

摘要: 3080 Introduction: Proprietary formulations containing the polysaccharide, hyaluronic acid (HA) utilise unique physiochemical and biological properties of HA enabling it to function as an excipient imparting its own pharmacological activity through directing entrained anticancer agent/s over-expressed CD44 receptors. Once localized in tumor, HA/drug complex aggregates forming a drug depot, increasing retention at site; subsequently efficacy is enhanced increased co-internalisation HA. In attempt overcome dose-limiting toxicities irinotecan (CPT-11), this was formulated with HA, resulting product called HyCAMP™. uncontrolled Phase l clinical trial HyCAMP™ metastatic colorectal patients incidence grade 3 or 4 diarrhea neutropenia less than has been observed other studies. The median patient survival study 16 months, compared expected ∼10 months based on historical controls. objective current elucidate potential mechanisms by which may be benefit over CPT-11 alone. Methodology: effect key metabolic enzymes determined incubating varying concentrations different MW (2, 10 & 860kDa) homogenates i) liver, ii) spleen, iii) kidney, iv) large small intestines v) 8 colon cancer cell lines . Colorimetric assays determine carboxylesterase (CE), β-glucuronidase (β-GLUC) uridine diphosphate glucuronosyl transferase (UDPGT) were conducted each tissue homogenate. Results: component formulation did not alter CE UDPGT but affect β-GLUC. both intestine 2kDa found exert inhibitory (70%) β-GLUC whereas 860kDa not. tumor line lysates physiological 860 kDa intra-tumoral (140%). Conclusions: influence involved metabolism irinotecan, effects seen tissues. If these data translate vivo , possible that GI-tract toxicity could where degradation products act inhibitor β-GLUC, competing SN-38G for active site conversion toxic SN-38. Conversely, high upregulates result greater metabolite SN-38, thereby CPT-11. Together two contribute towards therapeutic index CPT-11when presented formulation.