|Mahmoud el Kouni, Ph.D.|
The first is of studies on a detailed investigation of key enzymes of pyrimidine metabolism, mainly uridine phosphorylase and thymidine phosphorylase. His laboratory was responsible for detailed studies on these two enzymes and the development of a novel class of uridine phosphorylase inhibitors which have potentiative effects with clinically important antitumor (e.g. 5-fluorouracil and 5-fluoro-2'-deoxyuridine) and anti-AIDS (e.g. AZT) agents. He has been awarded 4 patents for the composition and use of these inhibitors. It is to his credit that one of these inhibitors is currently in Phase I clinical trials and a second in pre-clinical trials.
The usefulness of uridine phosphorylase inhibitors designed by Dr. el Kouni's group has already been established in the field of experimental chemotherapy of cancer and AIDS by various laboratories including his. These inhibitors were shown to enhance the efficacy of 5-fluoro-2'-deoxyuridine against human tumors in vitro and in vivo. Furthermore, they were shown to elevate the concentration and prolong the half-life of uridine in the plasma, as well as increase the salvage of uridine by various tissues. Therefore, these inhibitors were used to protect against or rescue from host-toxicity of anticancer (i.e. 5-fluorouracil) and anti-HIV (i.e. AZT) drugs, the toxicities of which were shown to be antagonized by administration of exogenous uridine or similar nucleosides. In this respect, uridine phosphorylase inhibitors can substitute, totally or partially, for the "uridine rescue regimens" in treating cancer, viral, and other diseases. uridine phosphorylase inhibitors alone or in combination with low concentrations of uridine can maintain adequate uridine concentration for a long enough time to rescue selectively the normal or uninfected cells from drug toxicity, without having to suffer from the toxic side effects (e.g. phlebitis, pyrogenic reactions, changes in body temperature and diarrhea) observed with the high concentration of uridine required to achieve the rescuing or protective effects in the absence of the inhibitor. The use of uridine phosphorylase inhibitors in manipulating uridine pool is not limited to the treatment of cancer or AIDS but can also be extended to treat other pathological and physiological disorders, where administration of uridine has been shown to be useful. Such disorders are quite numerous and include CNS disorders (e.g., cerebrovascular disorders, convulsions, etc.), sleep promotion, muscle performance, liver disease, cardiac damage, etc. The potential use of BBBA and other uridine phosphorylase inhibitors in treating such disorders has not yet been recognized in contemporary experimental or applied chemotherapy.
Dr. el Kouni's laboratory has also established the existence of circadian rhythm in several enzymes of pyrimidine metabolism, including uridine phosphorylase. The circadian rhythm of uridine phosphorylase was the opposite of that of plasma uridine levels and toxicity of 5-fluoro-2'-deoxyuridine. These results emphasize the importance of the time of administration of this important anti-cancer drug.
The other major area of Dr. el Kouni's research is application of his knowledge of purine and pyrimidine metabolism to the development of new therapeutic approaches for the treatment of schistosomiasis, toxoplasmosis and other parasitic diseases. Schistosomiasis ranks second behind malaria in prevalence as a human disease as it afflicts 200 million people in many parts of the world. Toxoplasmosis is the most commonly recognized of opportunistic infection of the CNS in immunocompromised patients such as those suffering from AIDS.
Dr. el Kouni is currently directing a systematic study of purine and pyrimidine metabolism in Toxoplasma gondii with the objective of identifying differences from mammalian metabolism that may be exploited for new chemotherapeutic approaches. Already he has made the important discovery of substantial differences in the metabolism of 6-substituted purine nucleosides in toxoplasma as compared to mammals. Toxoplasma metabolize these compounds to previously unknown toxic intermediates while mammalian systems do not. Administration of such compounds double the life span of animals infected with toxoplasma. A patent for the use of these compounds is currently pending.
el Kouni MH. Editorial, Potential Targets for the Rational Design of Antiparasitic Drugs. Curr Pharm Des 13: 553-554 (2007)
el Kouni MH. Adenosine metabolism in Toxoplasma gondii: Potential targets for chemotherapy. Curr Pharm Des 13:581-597 (2007) PMID: 17346176
Guarcello V, Blanquicett C, Naguib FN, el Kouni MH. Suppression of thymidine phosphorylase expression by promoter methylation in human cancer cells lacking enzyme activity. Cancer Chemother Pharmacol;62:85-96 (2008) PMID: 17805539
Choi JW, Shin CY, Choi MS, Yoon SY, Ryu JH, Lee JC, Kim WK, el Kouni MH, Ko KH. Uridine protects cortical neurons from glucose deprivation-induced death: Possible role of uridine phosphorylase. J Neurotrauma. 25:695–707 (2008) PMID: 18457515
Kim YA, Sharon A, Chu CK, Rais RH, Al Safarjalani ON, Naguib FN, el Kouni MH. Structure-Activity Relationships of 7-Deaza-6-benzylthioinosine Analogues as Ligands of Toxoplasma gondii Adenosine Kinase. J Med Chem 51:3934–3945 (2008) PMID: 18563892
Al Safarjalani ON, Rais RH, Kim YA, Chu CK, Naguib FN, el Kouni MH.7-Deaza-6-benzylthioinosine Analogues as Subversive Substrate of Toxoplasma gondii Adenosine Kinase: Activities and Selective Toxicities Biochem Pharmacol 76: 958-966 (2008) PMID: 18755159
Kim YA, Rawal RK, Yoo J, Sharon A, Jha AK, Chu CK, Rais RH, Al Safarjalani ON, Naguib FN, el Kouni MH Structure-Activity Relationships of Carbocyclic 6-Benzylthioinosine Analogues as Subversive Substrates of Toxoplasma gondii Adenosine Kinase. Bioorganic & Medicinal Chemistry 18:3403-3412 (2010) PMID: 20456959.
Al Safarjalani ON, Rais RH, Kim YA, Chu CK, Naguib FN, el Kouni MH. Carbocyclic 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase: Biological activities and selective toxicities Biochem Pharmacol 80:955-963 (2010) PMID: 20541538
Pulaa, WB, Dunn E. Garonnaa K, Watsona E, Hiranoc M, Pizzorno G, Schwartze EL, el Kouni MH,. Wheeler-Jones CPD. Paracrine stimulation of endothelial cell motility and angiogenesis by platelet-derived deoxyribose-1-phosphate. J Arteriosclerosis, Thrombosis, Vascular 12:2631-2638 (2010)
Al Safarjalani ON, Rais R,Naguib FNM, el Kouni MH. Potent Combination Therapy for Human Breast Tumors with High Doses of 5-Fluorouracil: Remission and Lack of Host-Toxicity. Cancer Chemother Pharmacol 69:1449–1455 (2012) PMID: 22373605