Therapeutic methods for inhibiting the growth of preneoplastic / neoplastic
vertebrate cells that abnormally express MN
protein are disclosed. Screening assays are provided for identifying compounds, preferably membrane-impermeant compounds, which inhibit the enzymatic activity of MN
protein / polypeptides and that are useful for treating patients with preneoplastic /
neoplastic disease. Further methods are disclosed for the preparation of positively-charged, membrane-impermeant heterocyclic sulfonamide CA inhibitors with high affinity for the membrane-bound
carbonic anhydrase CA IX. Preferred CA IX-specific inhibitors are aromatic and heterocylic sulfonamides, preferably that are membrane-impermeant. Particularly preferred CA IX-specific inhibitors are
pyridinium derivatives of such aromatic and heterocyclic sulfonamides. The CA IX-specific inhibitors of the invention can also be used diagnostically / prognostically for preneoplastic /
neoplastic disease, and for imaging use, for example, to detect
precancerous cells, tumors and / or metastases. The CA IX-specific inhibitors can be labelled or conjugated to radioisotopes for radiotherapy. The CA IX-specific inhibitors may be combined with conventional therapeutic anti-
cancer drugs, with other different inhibitors of
cancer-related pathways, with bioreductive drugs, or with radiotherapy to enhance the efficiency of each treatment. The CA IX-specific inhibitors may also be combined with CA IX-specific antibodies, preferably
monoclonal antibodies or biologically active
antibody fragments, more preferably humanized or fully human CA IX
monoclonal antibodies or biologically active fragments or such
monoclonal antibodies. Still further, the CA IX-specific inhibitors can be used for
gene therapy coupled to vectors for targeted delivery to preneoplastic / neoplastic cells expressing CA IX on their surfaces.