Most anti-neoplastic drugs have a narrow therapeutic window. Bone marrow suppression is frequently the major toxicity. We propose a combined basic and translational research program to establish new, more efficacious mutant enzymes for the protection of bone marrow in patients undergoing cancer chemotherapy. Our objective is to express the mutant enzymes in bone marrow stem cells to achieve greater protection against the toxicity of frequently administered chemotherapeutic agents than is afforded by the wild-type enzymes. Our approach is to utilize human enzymes involved in different aspects of DNA metabolism. Mutant O6-methylguanine - DNA methyltransferase (MGMT), acting at the level of DNA repair, will be used to increase resistance to alkylating agents. Mutant DNA polymerase eta (pol eta; pol eta) that can more efficiently bypass chemical modifications in DNA will be studied as a prototype polymerase for enhancing tolerance of unrepaired DNA lesions. Mutant, drug-resistant thymidylate synthase (TS), acting at the level of precursor formation for DNA synthesis, will be used to protect against the widely utilized substrate analog inhibitor 5-fluorouracil (5-FU). Mitigation of myelosuppression has tremendous potential benefits, including (1) adherence to regimens that are now interrupted or abandoned due to marrow toxicity, (2) toleration of higher drug doses than are currently employed, and (3) utilization of drug combinations that are too marrow-toxic to be useful at present.
| Prindle, Marc J; Fox, Edward J; Loeb, Lawrence A (2010) The mutator phenotype in cancer: molecular mechanisms and targeting strategies. Curr Drug Targets 11:1296-303 |
| Bielas, Jason H; Schmitt, Michael W; Icreverzi, Amalia et al. (2009) Molecularly evolved thymidylate synthase inhibits 5-fluorodeoxyuridine toxicity in human hematopoietic cells. Hum Gene Ther 20:1703-7 |
| Fox, Edward J; Salk, Jesse J; Loeb, Lawrence A (2009) Cancer genome sequencing--an interim analysis. Cancer Res 69:4948-50 |
| Chen, Cheng-Yao; Guo, Haiwei H; Shah, Dharini et al. (2008) Substrate binding pocket residues of human alkyladenine-DNA glycosylase critical for methylating agent survival. DNA Repair (Amst) 7:1731-45 |
| Loeb, Lawrence A; Bielas, Jason H; Beckman, Robert A (2008) Cancers exhibit a mutator phenotype: clinical implications. Cancer Res 68:3551-7;discussion 3557 |
| Venkatesan, Ranga N; Treuting, Piper M; Fuller, Evan D et al. (2007) Mutation at the polymerase active site of mouse DNA polymerase delta increases genomic instability and accelerates tumorigenesis. Mol Cell Biol 27:7669-82 |
| Bielas, Jason H; Loeb, Keith R; Rubin, Brian P et al. (2006) Human cancers express a mutator phenotype. Proc Natl Acad Sci U S A 103:18238-42 |
| Beckman, Robert A; Loeb, Lawrence A (2006) Efficiency of carcinogenesis with and without a mutator mutation. Proc Natl Acad Sci U S A 103:14140-5 |
| Venkatesan, Ranga N; Loeb, Lawrence A (2005) The multiplicity of mutations in human cancers. Adv Exp Med Biol 570:3-17 |
| Loh, Ern; Loeb, Lawrence A (2005) Mutability of DNA polymerase I: implications for the creation of mutant DNA polymerases. DNA Repair (Amst) 4:1390-8 |
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