Non-genotoxic selenium in the form of seleno-L-methionine is in clinical trials as an adjunct to conventional chemotherapy. In mice, dramatic cures of xenograft tumors were obtained using selenium in combination with chemotherapy drugs, cures associated with protection from dose-limiting toxicity of bone marrow and other tissues. Dose-limiting toxicity is a major impediment to cure rates of human patients. Selenium protected bone marrow while maintaining antitumor efficacy. Indeed, selenium allowed a doubling or even tripling of the maximum tolerated dose (MTD). It is clear that molecular determinants distinguish cancer cells from normal cells. One important molecular determinant, p53, is modified on key cysteine sulfhydryl residues in selenium-treated cells. Separate from its role in apoptosis, p53 is known to protect cells from DNA damage. Selenium was found to activate the protective functions of p53 and not apoptosis. The hypothesis is that p53 is a molecular target of selenium involved in bone marrow protection. The hypothesis will be tested by three specific aims:
Aim 1 will test the hypothesis that selenium protects p53-wildtype bone marrow from chemotherapy-induced myelosuppression by a DNA repair/cell cycle checkpoint mechanism, a mechanism lacking in mice lacking p53, and/or its downstream effector genes involved in DNA repair and cell cycle checkpoints.
Aim 2 will test the hypothesis that the mechanism whereby selenium protects wildtype mouse bone marrow is by a bona fide DNA repair/cell cycle checkpoint mechanism, and not an error-prone mechanism. Selenium is predicted to decrease mutagenesis.
Aim 3 will test the hypothesis that additional tissues may play a role in chemotherapeutic toxicity, i.e. if selenium protects the bone marrow, damage to other tissues may become dose-limiting. These studies will provide a molecular mechanism for bone marrow protection by selenium in combination with cancer chemotherapeutics, and will foster further clinical studies. ? ? ?
| Smith, Martin L; Kumar, M A Suresh (2010) The ""Two faces"" of Tumor Suppressor p53-revisited. Mol Cell Pharmacol 2:117-119 |
| Kumar, Ma Suresh; Pollok, Karen E; Smith, Martin L (2010) Selenomethionine or methylseleninic acid inhibits mutagenesis of a reporter gene in mouse bone marrow. Anticancer Res 30:291-3 |
| Hardy, Tabitha M; Kumar, Ma Suresh; Smith, Martin L (2010) RB stabilizes XPC and promotes cellular NER. Anticancer Res 30:2483-8 |
| Fischer, Joshua L; Kumar, M A Suresh; Day, Travis W et al. (2009) The Xpc gene markedly affects cell survival in mouse bone marrow. Mutagenesis 24:309-16 |
| Smith, Martin L; Kumar, M A Suresh (2009) Seleno-L-Methionine Modulation of Nucleotide Excision DNA Repair Relevant to Cancer Prevention and Chemotherapy. Mol Cell Pharmacol 1:218-221 |
