【摘 要】
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Despite advances in chemotherapeutic regimens, the treatment of metastatic cancer remains a challenge.A key problem with chemotherapy drugs is nonspecific drug distribution, resulting in low tumour co
【机 构】
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Department of Biochemistry and Molecular Biology Monash University Australia
【出 处】
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BITs 3rd Annual World Cancer Congress-2012(2012第五届世界癌症大会)
论文部分内容阅读
Despite advances in chemotherapeutic regimens, the treatment of metastatic cancer remains a challenge.A key problem with chemotherapy drugs is nonspecific drug distribution, resulting in low tumour concentrations and systemic toxicity.The holy grail of clinical cancer research has been to establish more specific ways of directing therapeutics to tumours,whether through more targeted anti-cancer agents or via the method of delivery.Many tumour cells show up-regulated expression of receptors for the polysaccharide hyaluronan (HA), resulting in HA having a high affinity for tumours.The primary tumour-related HA receptor is CD44 which is activated and over-expressed on greater than 95% of solid cancers.These observations have led to the clinical development of HA-derivatised cytotoxic drugs that use HA as the tumour recognition moiety.The drug delivery platform utilizes the large volumetric domain of HA to entrain small chemotherapeutic drugs and therapeutic within the 3-dimensional milieu.After intravenous administration the resultant HA/drug formulation accumulates in the microvascular of the tumour, forming a microembolism that increases drug retention at the tumour site and allows for rapid intracellular uptake of the drug complex via the activated CD44.Clinical development of three anti-cancer drugs has been undertaken and has demonstrated that such formulations are safe and efficacious.This presentation follows the pre-clinical and clinical development of this technology where mechanisms associated with;i) the mode of molecular interaction between HA and the chemotherapeutic drugs, ii)ability of HA to act as a targeted transport vehicle for anti-cancer agents, iii) effect of HA on the therapeutic index of chemotherapeutic drugs iv) the clinical safety and efficacy of these HA-based anti-cancer agents and vi) the regulatory approach which has enabled an accelerated development pathway are discussed.
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