Important note: Information in this article was accurate in 2003. The state of the art may have changed since the publication date.
PRNewswire - November 14, 2003
"These two studies underpin the rationale for Phase II clinical trials with CYC202 in glomerulonephritis," said Spiro Rombotis, CEO of Cyclacel. Further, this data highlights the potential of our approach to addressing cell proliferation disorders beyond cancer by specifically targeting key molecules that drive the process of cell division." Mr. Rombotis noted that CYC202 is also undergoing Phase IIa clinical trials in breast and lung cancers. CYC202 is the most advanced compound in the company's growing portfolio of cell cycle modulators.
Investigators from New York University's School of Medicine working with collaborators from Columbia University, Mount Sinai School of Medicine and Roswell Park Cancer Institute reported that CYC202 attenuated or reversed renal disease in a mouse model of collapsing glomerulopathy by targeting cell cycle progression. Tg-26 HIV-1 mice with a range of mild to severe renal disease received 75 mg/kg of CYC202 twice a day for 20 days. Following treatment, urinary, serological, and histopathological results showed that disease had reversed in 8 of 12 (67%) CYC202-treated mice and progressed in 10 of 12 controls. Unlike flavopiridol, another CDK inhibitor, amelioration of disease by CYC202 did not require suppression of HIV-1 transcription.
The investigators concluded that (a) CYC202 demonstrated a significant therapeutic benefit (p<0.05) and (b) that their results demonstrate a novel therapeutic strategy for collapsing glomerulopathy and broaden the range of proliferative kidney lesions that may respond to CYC202.
Collapsing glomerulopathy is an aggressive kidney disease defined by histopathology: glomerular collapse, visceral epithelial cell damage and characteristic tubulointerstitial changes. Patients present with severe nephrotic syndrome, marked proteinuria and rapid progression to chronic renal failure or death due to complications of nephrotic syndrome despite any form of treatment. It was first identified in 1994* and has emerged along with the HIV epidemic. Initially it was thought to be a consequence of HIV-associated nephropathy (HIVAN), a late stage complication of HIV infection with rapidly increasing incidence that is the most common cause of chronic kidney dysfunction and ultimately kidney failure in HIV-positive patients.
Collapsing glomerulopathy is now increasingly recognised in non-HIV patients as well. It can also develop in association with other viral infections, lymphoproliferative disorders, Systemic Lupus Erythematosus and other autoimmune diseases, other immune deficiency syndromes, and in the context of immunosuppressive drug therapy.
Investigators from the University of Aachen, Germany reported that CYC202 was effective in a model of membranous nephritis and can be administered in renal diseases characterised by podocyte injury. Rats with an experimental rat model of membranous nephritis, called passive Heymann nephritis were treated (day 3 to 30) with low (25 mg/kg/day) or high (50 mg/kg/day) doses of CYC202. Podocyte desmin expression was markedly upregulated in almost all glomeruli and not significantly different between the three groups. No tubulointerstitial damage was noted in any group. Biological activity of CYC202 was observed at day 30 as a dose dependent decrease in glomerular mitosis (-22% at low and -61% at high dose vs. control). CYC202 activity in vivo was further noted as numbers of mitotic cells in the tubulointerstitium decreased significantly after low dose CYC202 at day 9 and high dose at days 9 and 30.
The investigators concluded that (a) CYC202 treatment caused a decrease in cell proliferation in both the glomerulum and the interstitium, indicating the potential for CYC202 to beneficially control the excessive cell division that contributes to kidney failure, and (b) CYC202 can be safely administered in renal diseases characterised by podocyte injury, as it did not decrease podocyte numbers.
Glomeruli are the kidney's filtering units and about 1 million of them exist in each kidney. Membranous nephropathy (also called membranous nephritis or membranous glomerulonephritis) is a kidney disease in which inflammation of the glomeruli causes the glomerular filtering layer (Glomerular Basement Membrane) to become thickened causing protein to leak into the urine. When this leak is severe, the disease is called nephrotic syndrome. The diagnosis of membranous nephropathy requires a kidney biopsy. Membranous nephropathy is a primary renal disease of uncertain origin and may be associated with other conditions such as hepatitis B, malaria, malignant solid tumours, non- Hodgkin's lymphoma, Systemic Lupus Erythematosus, as well as toxic exposure to gold, mercury, penicillamine, trimethadione, skin-lightening creams, and others.
Podocytes are slowly proliferating kidney cells that are essential for the recovery of kidney function following injury. Podocyte depletion is a likely cause of glomerular sclerosis and eventual kidney failure. Since podocytes express CDK, the German investigators tested whether CDK inhibition by CYC202 affects podocytes.
About Cyclacel (http://www.cyclacel.com)
Cyclacel is a biopharmaceutical company that designs and develops small molecule drugs that act on cell cycle regulators to stop uncontrolled cell division in cancer and other diseases involving abnormal cell proliferation.
Cyclacel discovery integrates cell cycle biology with a library of gene-based targets, RNAi functional genomics, chemogenomics and clinical biomarker technologies to rapidly deliver new drugs. The most advanced of Cyclacel's 8 research and development programs is CYC202, a Cyclin Dependent Kinase Inhibitor (CDKI), in Phase IIa trials for breast and lung cancer. CYC202 is also being explored for use in glomerulonephritis, an inflammatory disease associated with kidney cell proliferation. CYC400, 2nd generation CDKIs, and CYC381, a clotrimazole analogue, acting on the cancer cell cycle are in preclinical development. Cyclacel has entered into corporate alliances with AstraZeneca, CV Therapeutics, Lorus Therapeutics and a top 5 pharmaceutical major all in the oncology field.
Notes to Editors:
American Society of Nephrology - Renal Week 2003 Conference, November 12-17, 2003; San Diego Convention Center, San Diego, California (http://www.asn-online.org).
1. Poster Number: SA-FC118. Reversal of Collapsing Glomerulopathy in Mice with the Cyclin-Dependent Kinase Inhibitor CYC202. Authors: Peter J. Nelson, Dana Gherardi, Vivette D. DAgati, Te-Hua T. Chu, Anna Barnett, Athos Gianella-Borradori, Irwin H. Gelman. Date/Time: Saturday, November 15, 2003 - 5:45 PM. Session Info: Free Communication: Molecular Basis of Glomerular Diseases (4:00 PM-6:00 PM).
2. Poster Number: SA-PO194. Inhibition of Cyclin Dependent Kinase-2 (CDK2) by CYC202 (R-Roscovitine) Decreases Cell Proliferation but Does Not Aggravate Podocyte Injury in Experimental Membranous Nephropathy. Authors: Maja Milovanceva-Popovska, Uta Kunter, Tammo Ostendorf, Arndt Petermann, Song Rong, Anna Barnett, Juergen Floege. Date/Time: Saturday, November 15, 2003 - 10:00 AM Session Info: Poster: Cell Proliferation (10:00 AM-12:00 PM).
Cyclacel(R), Fluorescience(R), Penetratin(R) and Polgen(R) are registered trademarks.
* Detwiler et al, Kidney International, 1994:45:1416-1424.
SOURCE Cyclacel Limited
Web Site: http://www.cyclacel.com
http://www.asn-online.org
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