Chadha, Kailash C., PhD

Associate Member, Department of Molecular and Cellular Biology
Roswell Park Cancer Institute
Elm and Carlton Streets
Buffalo New York USA 14263
Tel: 716-845-3101
Fax: 716-845-8389
E-mail: kailash.chadha@roswellpark.org

Education
BSc, Biology, University of Rajasthan, Jaipur India, 1962
MSc, Plant Pathology, Microbiology, I.A.R.I., New Delhi India, 1964
PhD, Virology, Biochemistry, University of Guelph, Ontario Canada, 1968

Description of Research

A. “Biology of Interferon System”

B. “Biomarkers for Early Detection and Management of Prostate Cancer and Role of PSA in prostate tumor progression & Metastasis”

Program 1. Interferons have significant antiviral, antiproliferative and immunoregulatory activities. Interferons have been used for the treatment of many viral and non-viral malignancies. However, the response to treatment with interferons has been variable. Some patients respond favorably, while others fail to respond. We have shown that this variable response is partially due to the presence of interferon inhibitory activity in their blood circulation. Our laboratory is involved in the isolation and molecular characterization of this interferon inhibitory factor(s).

Progress

Interferon inhibitory activity in the blood circulation of late stage cancer HIV‑1 infected patients and in MS patients is due to: a) interferon inhibitory protein; b) high levels of PGE2; c) high levels of soluble interferon receptor; or d) any combination of these factors.

Selected Publications

Chadha KC, Schwartz SA, Nair MPN, Demeter LR, Hewitt RG. Serum interferon inhibitor declines in patients with HIV-1 infection after a change in antiretroviral therapy. Immunol Invest 32(4):299-312, 2003.
Chadha K, Weinstock-Guttman B, Zivadinov R, Bhasi K, Muhitch J, Feichter J Tamano-Blanco M, Abdelrahman N, Ambrus Sr J, Munschaeur F, Ramanathan M. Interferon Inhibitory Activity in Multiple Sclerosais Patients. Arch Neurology 63:1579-1584, 2006.

Program 2. C57BL/6 mice maintained on alcohol containing diet had lower levels of T‑cells including CD4+. Splenocytes from these animals produced significantly low levels of IFN‑alpha and IFN‑gamma but did not differ in their NKC activity. Mice infected with LP‑BM5MuLV virus showed progressive splenomegaly, leukopenia, lymphadenopathy, and suppression in vitro of anti-SRBC response. IL‑2-mediated response of splenocytes did not differ significantly from uninfected controls. Spleen cell proliferation elicited by mixture of phorbol and IL‑2 or phorbol and ionomycin was significantly inhibited. We have observed that cocaine is a significant cofactor in the pathogenesis of HIV infection primarily because it increases susceptibility to and progression of HIV‑1 infection by inhibiting the synthesis of HIV‑1 protective chemokines and/or upregulating the HIV‑1 entry co-receptor, CCR5.

Selected Publications

Nair MPN, Kandaswami C, Mahajan S, Chadha KC, Chawda R, Nair N, Kumar N, Schwartz SA. The flavonoid, Quercetin, differentially regulates Th‑1 (IFN‑g) and TH‑2 (IL‑4) cytokine gene expression by normal peripheral blood mononuclear cells. Biophys Biochem Acta 1593:29-36, 2002.
Ambrus JL Sr, Chadha KC, Islam A, Akhter S, and Ambrus JL Jr. Treatment of viral and neoplastic diseases with double-stranded RNA derivatives and other new agents. Mini Review: Expt Biol Med 231:1283-1286, 2006.

Program 3. Prostate Cancer: Relevance of PSA and PSMA in Early Diagnosis. Role of PSA in prostate tumor tissue and its relevance to prostate tumor growth and metatasis. Prostate cancer has the highest incidence of any non-cutaneous malignancy in the Western world and is the second leading cause of cancer related deaths in men. PSA is a well-recognized marker for the early diagnosis and management of prostate cancer. However, it is not disease specific and results in many false positives. Our objective is to develop new methodology that will be more sensitive and will eliminate the risk of false positives. The physiological reasoning for the rise in PSA level in prostate cancer patients is not well understood. PSA seems to have a role in angiogenesis.

Progress

We have shown that PSA and its molecular complexes have an affinity for thiophilic gels (T‑gel). T‑gel affinity can be exploited for PSA purification as well as for obtaining serum-based PSA standard that will have both free PSA and its complexes.

We have developed methodology that permits measurement of PSMA in the sera of prostate cancer patients. Such a task has never been accomplished before. Our test will effectively eliminate false positives and therefore will eliminate unnecessary biopsies. We are currently testing additional samples to validate our test procedures.

In our primary studies, we have shown that treatment of human prostate cancer cells with PSA modulates factors, su. Prostate cancer has the highest incidence of any non-cutaneous malignancy in the western world and is the second leading cause of cancer related deaths in men. Prostate-Specific Antigen (PSA) is a well-recognized biomarker for the early diagnosis and management of prostate cancer. However, PSA test is neither disease specific nor tissue specific and results in >70% false positive. There are two major areas of research in my laboratory: one involves development of new biomarkers that will be more selective and specific and includes PSMA, IL-8, TGF-beta, etc., and the second area involves in determining if PSA has a physiological role as an anti-angiogenic molecule. In our preliminary studies, we have shown that human prostate cells that are highly malignant have higher levels of expression of pro-angiogenic growth factors such as VEGF, IL-8, TGF-beta, bFGF, etc. and low levels of anti-angiogenic factors such as interferons and angiostatin. The treatment of these cells with PSA results in down regulation of pro-angiogenic factors and up regulation of anti-angiogenic factors. We have now shown in a xenograft model that exogenously administered PSA can significantly reduce tumor growth. This suggests that PSA has a potential to be used as therapeutic modality to treat prostate cancer.

Selected Publications and Patents

Chadha KC, Sulkowski E, Kawinski E. A method for detecting PSA and its molecular forms using thiophilic gel. U.S. Patent Application # 09,624,692. Patent, awarded 12/5/01.
Kawinski E, Chadha KC. Detection of prostate specific membrane antigen (PSMA) in the sera of prostate cancer patients. U.S. Patent #09/09/624/692.
Kawinski E, Levine E, Chadha KC. Thiophilic interaction chromatography facilitates detection of various molecular complexes of prostate-specific antigen in biological fluids. Prostate 50(3):145-153, 2002.
Alinkeel RK, Nair MPN, Sufrin G, Mahajan SD, Chadha KC, Chawda RP, Schwartz SA. Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res 64:5311-5321, 2004.
Bindukumar B, Kawinski E, Cherrin C, Gambino LM, Nair MPN, Schwartz SA, Chadha KC. Two-step procedure for purification and characterization of enzymatically active rostate-specific antigen from seminal plasma. J Chromatogr B. 813:113-120, 2004.
Bindukumar B, Schwartz SA, Nair MPN, Aalinkeel R, Chadha KC. Prostate-specific antigen (PSA) modulates the expression of genes involved in prostate tumor growth. Neoplasia 7(3):241-252, 2005.

Selected Publications (please click here for a complete PubMed list for Dr. Chadha).