Novel Thymidylate Synthase Mutants for Treating Chemotherapy-induced Mucositis and Other Chemotherapy Side Effects

Introduction 35 novel thymidylate synthase (TS) mutants have been generated by random mutagenesis. These mutants are different from wild type TS in single, double, or multiple mutations, which are located distant from the active center. The new TS mutants reveal enhanced resistance to TS-inhibiting drugs, like 5-fluorouracil (5-FU) and 5-fluoro-2-deoxyuridine monophosphate (FdUMP), which are frequently used for cancer chemotherapy. All these mutants can be used for protection of normal human cell populations against the toxic manifestation of analogs that inhibit TS. Technology description Drugs that inhibit thymidylate synthase (TS) have been used in cancer chemotherapy for approximately 40 years. 5-fluorouracil (5-FU) is effective either as a single agent or in combination with other drugs for the treatment of various types of carcinomas, such as breast or colon cancer. TS is an essential enzyme that catalyzes the methylation of dUMP to dTMP. In human cells, DNA synthesis is dependent on the production of dTMP by this de novo pathway (Kornberg and Baker, DNA replication, 1992). In addition, it is known that TS activity is highest in rapidly proliferating cells, such as tumor cells but also normal cells of mucous membranes and other fast growing normal cell types. Therefore, the growth inhibiting effects of chemotherapeutic TS-inhibitors are not limited to cancer cells but also cause severe damage and death of normal cells. Severe side effects of TS inhibitors, such as toxicity to bone marrow and specifically an inflammation of the mucous membranes of the gastrointestinal tract (mucositis) may require a decrease of the dosage or time period of the cancer chemotherapy. Due to the importance of TS-inhibitors in cancer therapy there is an urgent need for new resistant mutants, which can protect normal human cell populations against the toxic manifestations of analogs that inhibit TS. Objective of this invention was to generate novel thymidylate synthase enzymes that reveal enhanced resistance to 5-FU, FdUMP, and related drugs and to make them available for therapeutic use. The human TS gene was mutated by error-prone PCR. TS mutants with single, double, or multiple mutations were generated, which are resistant to significantly higher concentrations of TS-inhibitors than wild type TS. The delivery of these resistant TS mutant into normal cells will reduce or prevent clinically severe side effects, which are associated with cancer chemotherapy using TS inhibitors. Business opportunity This invention represents mutant key enzymes, which are resistant to thymidylate synthase inhibitors. These mutant enzymes can be used to design drugs for the local prevention and/or treatment of chemotherapy-associated side effects due to cancer chemotherapeutic TS-inhibitors, such as a mucositis of the gastrointestinal tissues or toxicity to bone marrow cells. Intellectual property position European and U.S. patent applications are pending.

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