Varsha Gandhi, Ph.D.

M.D. Anderson Cancer Center
The University of Texas
M.D. Anderson Cancer Center
1515 Holcombe Blvd., Box 428
Houston, Texas 77030
(713) 745 2376
http://www.mdanderson.org

The major objective of Dr. Gandi's program is to improve the therapeutic activity of anticancer drugs, specifically nucleoside analogues, by understanding their metabolism, mechanisms of action, and interactions in combinations. This approach provides the basic scientific knowledge about these compounds and also furnishes important information in the design of new clinical protocols. Because nucleoside analogues are the most effective agents for treatment of hematologic malignancies, the focus of our clinical and basic research is leukemias.

Initial basic research efforts centered on modulating the metabolism of arabinosylcytosine (ara-C) by fludarabine to potentiate the accumulation of ara-C triphosphate in the target cells. These in vitro investigations provided a biochemical rationale for combining these 2 antimetabolites. Additional ex vivo studies established the feasibility of this combination.

Based on these data, clinical trials were designed and conducted for patients with relapsed acute and chronic leukemias. The pharmacokinetic and pharmacodynamic end points provided knowledge about optimal schedule, drug dosage, and duration of infusions for this regimen. This strategy has been used nationally and internationally.

Additionally, a flurry of new clinical protocols incorporated the fludarabine and ara-C couplet with DNA-damaging agents, such as mitoxantrone, cisplatinum, and idarubicin. Mechanistic studies provided information about the actions of fludarabine phosphate on potentiating the metabolism and action of ara-C triphosphate, the active metabolite of ara-C. A similar biochemical modulation strategy has been employed for combining other active agents, such as hydrea, chlorodeoxyadenosine, or gemcitabine, with ara-C.

They are also developing a new nucleoside analogue, arabinosylguanine, in both the laboratory and the clinic. In the initial phase I trials, this drug is showing efficacy in heavily pretreated patients, specifically those with B-cell chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia. Their focus is to determine the biochemical, pharmacologic, pharmacodynamic, and molecular end points that mediate the specificity of this drug.

These actions and interactions provide molecular end points for the cytotoxicity observed during therapy. An additional target for the cytotoxicity of most of these analogues is the inhibition of ribonucleotide reductase. This enzyme provides precursors for DNA synthesis needed during the replication and repair of DNA. Their investigations also focus on the fate of this protein during DNA replication and repair and on the role of nucleoside analogues in perturbing this machinery. Knowledge gained from these studies will be used in the optimal design of clinical protocols using inhibitors of ribonucleotide reductase and other chemotherapeutic agents targeted toward DNA.

In collaboration with colleagues at the Robert H. Lurie Comprehensive Cancer Center (Chicago, IL), Dr. Gandi is developing 8-chloro-adenosine, an RNA-directed nucleoside analogue. Her initial studies provided evidence that halogenated cAMP serves as a prodrug for 8-chloro-adenosine, which, as its triphosphate, affects RNA synthesis. With DNA microarray analyses, they identified the genes whose transcription is inhibited by this analogue.

Dr. Gandi plans to develop this agent for treatment of indolent leukemias, multiple myeloma, and solid tumors.

Selected Publications

• Gandhi V, Ayres M, Halgren RG, Krett NL, Newman RA, Rosen ST. Metabolism and action of 8-chloro-cAMP and 8-chloro-adenosine in multiple myeloma. Cancer Res 61:5474-5479, 2001
• Gandhi V, Plunkett W, Weller S, Du M, Ayres M, Rodriguez Jr CO, Ramakrishna P, Rosner GL, Hodge JP, O'Brien S, Keating MJ. Evaluation of the combination of nelarabine and fludarabine in leukemias: Clinical response, pharmacokinetics and pharmacodynamics in leukemia cells. J Clin Oncol 19:2142-2152, 2001
• Kisor DF, Plunkett W, Kurtzberg J, Mitchell BS, Hodge JP, Ernst T, Keating MJ, Gandhi V. The pharmacokinetics of 506U78 and ara-G in pediatric and adult patients during a phase I study of 506U78 for the treatment of refractory hematologic malignancies. J Clin Oncol 18:995-1003, 2000
• Rodriguez CO Jr, Gandhi V. Arabinosylguanine-induced apoptosis of T-lymphoblastic cells: Incorporation into DNA is a necessary step. Cancer Res 59:4937-4943, 1999
• Rodriguez CO Jr, Legha JK, Estey E, Keating MJ, Gandhi V. Pharmacological and biochemical strategies to increase the accumulation of arabinofuranosylguanine triphosphate in primary human leukemia cells. Clin Cancer Res 3:2107-2113, 1997