Associate Professor of Oncology
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo, New York 14263
Tel: (716) 845-3287
E-mail: lakshmi.pendyala@roswellpark.org

Education
University of Western Ontario, London, Ontario, Canada, (PhD, 1974)

Description of Research
Research studies in my laboratory are on the drug action and resistance mechanisms of platinum complexes using in vitro models and also on the pharmacology of anticancer agents being evaluated in initial clinical trials and translational studies. Oxaliplatin, a diaminocyclohexane platinum complex, non-cross resistant to cisplatin and exhibits activity in GI cancers has been a study focus of this laboratory for a number of years. Using oxaliplatin resistant cell lines isolated in our laboratory as models, we have demonstrated that glutathione mediated drug detoxification and defects in drug accumulation are the major mechanisms involved in oxaliplatin resistance. To gain better insights into the mechanisms of drug action and mechanisms of resistance we have carried out Affymetrix Oligonucleotide Array Analysis of human tumor cell lines treated with platinum agents. These studies have identified a large number of genes to be up- or down-regulated following a 2h treatment of human ovarian carcinoma cells with oxaliplatin or cisplatin. The up- or down- regulation was progressive with time and was highest at 16 to 24h following the drug treatment. Genes with altered expression included those related to DNA damage response, cell cycle progression, signal transduction, apoptosis, DNA repair and enzymes affecting certain metabolic pathways. Some of the effects of platinum drugs, especially on certain metabolic pathways are of clinical pharmacological interest and have never been studied before and are being pursued currently in my laboratory. One area of current pursuit is platinum drug effects on the polyamine pathway.

Polyamines are essential for cell survival. Depletion of intracellular polyamine pools results in inhibition of cell growth, making the polyamine pathway a potential therapeutic target. Our finding that platinum agents are potent inducers of Spermidine/Spermine N¹-acetyltransferase (SSAT) mRNA, and that combining the clinically tested polyamine analog N¹, N¹¹ diethylnorspermine (DENSPM) with oxaliplatin produces a synergistic increase in SSAT activity and a significant depletion of cellular polyamine pools has initiated a new area of the platinum polyamine interaction studies in my laboratory. We identified it as an important area to pursue because of its clinical relevance. We believe the observed mechanistic synergy between oxaliplatin and DENSPM could be translated into effective treatment strategy with appropriate in vitro and in vivo optimization.

Other interests include preclinical/clinical pharmacokinetic, pharmacodynamic studies in cancer drug development and translational studies. A translational study whose major goal was to explore correlations between gene expression and survival in esophageal cancer patients receiving oxaliplatin based therapy identified XPA, a DNA repair gene to be a potential predictor for survival and TS, g-GCS and ERCC-1 to be potential proliferation markers.

Selected Relevant Publications

• Hector, S., Porter, C.W., Kramer, D. L., Clark, K., Prey, J., Kiesel, N., Diegelman, P., Chen, Y and Pendyala, L. Polyamine catabolism in platinum drug action: Interactions between oxaliplatin and the polyamine analogue N1, N11-diethylnorspermine at the level of spermidine/spermine N1-acetyltransferase. Molecular Cancer Therapeutics, 3:813-822, 2004.
• Azrak, R, Cao, S., Slocum, H, Toth, M.D, Durrani, FA.,Yin, M,., Pendyala, L., Zhang, W, Mcleod, H.L., and Rustum, YM. Therapeutic synergy between irinotecan and 5fluorouracil against human tumor xenografts. Clinical Cancer Research, 10:121-1129, 2004
• N Ramnath, N Khushalani, K Toth, A Liwin, M. Intengan, H Slocum, L. Pendyala, P Smith, C Stewart, J Hoffman, M Javle, J Berdzik, P Creaven and Y Rustum. S-Phase Modulation by Irinotecan: Pilot Studies in Advanced Solid Tumors. Cancer Chemotherapy and Pharmacology, 2004 (In Press).
• L. Leichman, D. Lawrence, K. Clark, H. Nava, E. Nava, C. G. Leichman, G. Proulx, J. Berdzik, W. Greco and L. Pendyala. Updated results of an exploratory gene expression analysis for primary esophageal cancer (PEC) patients (pts) treated with oxaliplatin (OXP), protracted infusion (PI) 5FU and radiation (XRT). Proc. ASCO. 204:316, 2004 (Manuscript in Preparation)
• Pendyala, L., Schwartz, G., Smith, P., Zdanowicz, J., Murphy, M., and Hausheer, F. Modulation of plasma thiols and mixed disulfides by BNP7787 in patients receiving paclitaxel/cisplatin therapy. Cancer Chemotherapy and Pharmacology 51: 376-384, 2003
• Smith, P.F., Booker, B.M., Creaven, P.J., Perez, R and Pendyala, L. Pharmacokinetics and Pharmcodynamics of mesna-mediated plasma cysteine depletion. J. Clinical Pharmacology. 43: 1324-1328, 2003
• Hector, S., Bolanowska-Higdon, W., Zdanowicz, J., Hitt, S and Pendyala, L. In vitro studies on the mechanisms of oxaliplatin resistance. Cancer Chemotherapy Pharmacology, 48: 398-406, 2001