Cisplatin is one of the most widely used chemotherapeutic drugs. It is primarily used in the treatment of testicular, ovarian, head and neck and lung cancers. The cytotoxic effects of cisplatin have been attributed to DNA adducts which block the enzymes involved in DNA replication and DNA transcription. These adducts cause cell cycle arrest which eventually leads to apoptosis. Frequently, however, after treatment and remission of the cancer, recurrence and resistance to cisplatin occurs. A major mechanism of this resistance in tumor cells is enhanced DNA repair. This proposal focuses on the pathways that play a role in cisplatin effectiveness. We hypothesize that base excision repair (BER) and mismatch repair (MMR) play vital roles in maintaining cisplatin sensitivity through a unique mechanism that is dependent on interstrand cross-links (ICLs). This mechanism is mediated through specific structural processing of the ICLs and competition with 'actual'repair of the ICL damaged DNA. To address our hypothesis, we will conduct the following specific aims 1) elucidate the role of BER proteins in cisplatin sensitivity and ICL repair;2) determine the role of MMR proteins in cisplatin sensitivity, ICL repair and mutation avoidance;and 3) use in vitro techniques and purified proteins to further assess the biochemical mechanisms of BER and MMR proteins in cisplatin ICL processing. It is critical to understand the pathways involved in cisplatin efficacy and mechanisms that cancer cells develop to overcome the drug. This is imperative for the design of better treatment protocols as well as in the development of new anticancer agents. Without this understanding, the development of new cancer treatment is limited.

Public Health Relevance

Cisplatin and other platinum based chemotherapeutic drugs are the most widely used and effective cancer drugs today, but clinical limitations, especially cancer drug resistance, are a major health concern. The goal of this proposal is to understand the mechanisms and pathways involved in cisplatin effectiveness and resistance. This is imperative for the design of better treatment protocols as well as in the development of new anticancer agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM088249-03
Application #
8265820
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Janes, Daniel E
Project Start
2010-03-15
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$282,093
Indirect Cost
$84,306
Name
University of Toledo
Department
Biochemistry
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Kothandapani, Anbarasi; Patrick, Steve M (2013) Evidence for base excision repair processing of DNA interstrand crosslinks. Mutat Res 743-744:44-52
Kothandapani, Anbarasi; Sawant, Akshada; Dangeti, Venkata Srinivas Mohan Nimai et al. (2013) Epistatic role of base excision repair and mismatch repair pathways in mediating cisplatin cytotoxicity. Nucleic Acids Res 41:7332-43
Kothandapani, Anbarasi; Dangeti, Venkata Srinivas Mohan Nimai; Brown, Ashley R et al. (2011) Novel role of base excision repair in mediating cisplatin cytotoxicity. J Biol Chem 286:14564-74