摘要
Carbonic anhydrases(CA, EC 4.2.1.1) catalyze the interconversion bewteen carbon dioxide and bicarbonate with generation of protons. The carbonic anhydrase isozyme Ⅸ(CA Ⅸ) is highly overexpresed in hypoxic tumors and shows very restricted expression in normal tissues. CA Ⅸ is a dimeric protein possessing very high catalytic activity for the hydration of carbon dioxide to protons and bicarbonate. Its quaternary structure is unique among members of this family of enzymes, allowing for structure-based drug design campaigns of selective inhibitors. Inhibition of CA Ⅸ with sulfonamide and/or coumarin inhibitors was recently shown to lead to a potent retardation for the growth of both primary tumors and metastases. Some fluorescent sulfonamides were shown to accumulate only in hypoxic tumor cells overexpressing CA Ⅸ, and might be used as diagnostic tools for imaging of hypoxic cancers. Sulfonamide inhibitors were also more effective in inhibiting the growth of the primary tumors when associated with irrdiation. CA Ⅸ is thus both a diagnostic and therapeutic validated target for the management of hypoxic tumors normally non-responsive to classical chemio- and radiotherapy.
Carbonic anhydrases(CA, EC 4.2.1.1) catalyze the interconversion bewteen carbon dioxide and bicarbonate with generation of protons. The carbonic anhydrase isozyme Ⅸ(CA Ⅸ) is highly overexpresed in hypoxic tumors and shows very restricted expression in normal tissues. CA Ⅸ is a dimeric protein possessing very high catalytic activity for the hydration of carbon dioxide to protons and bicarbonate. Its quaternary structure is unique among members of this family of enzymes, allowing for structure-based drug design campaigns of selective inhibitors. Inhibition of CA Ⅸ with sulfonamide and/or coumarin inhibitors was recently shown to lead to a potent retardation for the growth of both primary tumors and metastases. Some fluorescent sulfonamides were shown to accumulate only in hypoxic tumor cells overexpressing CA Ⅸ, and might be used as diagnostic tools for imaging of hypoxic cancers. Sulfonamide inhibitors were also more effective in inhibiting the growth of the primary tumors when associated with irrdiation. CA Ⅸ is thus both a diagnostic and therapeutic validated target for the management of hypoxic tumors normally non-responsive to classical chemio- and radiotherapy.
基金
Supported by The 7th Framework Programme Grant of the European Union Metoxia
