PROGRESS IN IDENTIFYING CLINICAL RELEVANCE OF INHIBITION, STIMULATIONAND MEASUREMENTS OF POLY ADP-RIBOSYLATION

Our laboratory, in collaboration with Oxigene Inc, has been involved i n identifying commercially feasible clinical applications of measureme nt or modulation of ADP-ribosylation as a core technology. For this pu rpose a pivotal regulatory role for ADP-ribosylation in the repair of DNA lesions leading to cytotoxic as well as mutagenic events has been hypothesized. A new class of DNA repair inhibitors, the N-substituted benzamides, has been identified which can react with radiation to prod uce reactive intermediates that oxidize thiol amino acids. Their propo sed mechanisms of action are two-fold: ie they can interact with radia tion: i) to directly enhance DNA damage; and ii) to react with thiols in the zinc finger DNA binding domain of poly ADP-ribosyl transferase to inhibit DNA repair and thereby increase DNA damage. Sensamide, a cl inically relevant formulation of metoclopramide which is an N-substitu ted benzamide, has indicated enhancement of tumor response and surviva l in patients with inoperable squamous cell carcinoma of the lung when it was administered as a radiosensitizer in a phase I/II trial and co mpared to historical controls. A mechanism of endogenous regulation of human mononuclear leucocyte ADP-ribosylation has been identified to b e HOCl/N-chloramine production via the oxidative burst of phagocytes. HOCl/N-chloramines are potent oxidants of thiol-containing proteins. Q uantitative estimation of N-chloramine sensitive plasma thiols has bee n identified as an effective surrogate measure of leucocyte poly ADPRT . Dietary factors and other chemical agents such as tamoxifen that can inhibit HOCl/N-chloramine production by phagocytes are being identifi ed as drugs that can enhance ADP-ribosylation, and thus prevent DNA da mage accumulation which in turn is thought to influence the developmen t of age associated diseases.