BIOCHEMISTRY

Dr. Martina Veigl

Associate Professor

• Biochemistry Trainer: NO
  
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• Phone: 216 368 5689
  
• Fax: 216 368 8919
  
• Office: Wolstein 3rd Floor
  
• Lab: Wolstein 3rd Floor
  
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• Mail Address:
  
Case Cancer Center
10900 Euclid Avenue
Cleveland, OH 44106-7285

Pub Med:

Dr. Dr. Martina Veigl

Work in Dr. Veigl's laboratory is focused on study of mechanisms underlying: 1) BCNU-induced G:C A:T and G:C T:A point mutations [the major mutagenic damage resulting from BCNU exposure determined in our previous studies], 2) mutations resulting from treatment of sickle cell anemia patients with hydroxyurea and 3) frameshifts and point mutations resulting from deoxynucleotide pool perturbations.

We are in collaborative efforts to investigate the apparent mutator activity in cell lines established from patients with hereditary non-polyposis colon cancer [HNPCC], as well as two other projects. These projects are focused on study of alterations in sensitivity and/or resistance of cells following repeated exposure to ionizing radiation and delineation of the sequence specificity of deletion mutations induced by doxorubicin.

1) Studies of BCNU-induced damage and mutations are attempting to dissect mutation-inducing effects from the cytotoxic properties of this interesting chemotherapeutic agent. BCNU is an important agent for study because it demonstrates unique efficacy a mong alkylating agents for inducing remissions of malignant gliomas and advanced colon cancer. However, the utility of this drug is limited by its propensity to cause mutation and secondary tumors in animals and by current inabilities to effect cure of t umors with this agent. Dr. Veigl's studies are exploiting DNA repair deficient cell lines, vectors carrying the gene for alkyltransferase, specific analogs incapable of crosslinking and in vitro systems using BCNU damaged templates to delineate the mutag enic versus toxic mechanisms of this chemotherapeutic agent.

2) Hydroxyurea is now being evaluated for use as an agent to ameliorate pain crisis in sickle cell anemia patients. Hydroxyurea, however, causes profound reduction in deoxynucleotides precursor pools as a result of its effects on ribonucleotide reducta se. Studies in this project will explore possible mutagenic effects of hydroxyurea on the hprt gene of T-lymphocytes in patients undergoing treatment with this drug.

3) A program to study the mechanisms through which deoxynucleotide pool imbalance leads to mutations is ongoing. This work is important because many chemotherapeutic agents in clinical use [i.e. antifolates, alkylators, nucleotide analogues, hydroxyure a, etc] lead to profound alterations in nucleotide pools during treatment. This project utilizes site specific mutation approaches to determine the role of DNA sequence in directing pool imbalance- induced mutations through DNA polymerase dependent processes.

Selected References

• R.D. Anderson, M.L. Veigl, J. Baxter and W.D. Sedwick. Excision repair reduces doxorubicin-induced genotoxicity. Mutation Research 294, 215-222. (1993)

• R.D. Anderson, C.Y. Bao, D.T. Minnick, J. Baxter, M.L. Veigl and W.D. Sedwick. Sequencing of double-stranded polymerase chain reaction products for mutation analysis. Mutation Resarch 288, 181-185. (1993)

• D.T. Minnick, S.L. Gerson, L.L. Dumenco, M.L. Veigl and W.D. Sedwick. Specificity of bischloroethylnitrosourea-induced mutation in a Chinese hamster ovary cell line transformed to express human O6-alkylguanine-DNA alkyl transferase. Cancer Research 53, 997-1003. (1993.