Progress in identifying clinical relevance of inhibition, stimulation and measurements of poly ADP-ribosylation.
Our laboratory, in collaboration with Oxigene Inc, has been involved in identifying commercially feasible clinical applications of measurement or modulation of ADP-ribosylation as a core technology. For this purpose 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 produce reactive intermediates that oxidize thiol amino acids. Their proposed mechanisms of action are two-fold: ie they can interact with radiation: 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 clinically relevant formulation of metoclopramide which is an N-substituted benzamide, has indicated enhancement of tumor response and survival in patients with inoperable squamous cell carcinoma of the lung when it was administered as a radiosensitizer in a phase I/II trial and compared to historical controls. A mechanism of endogenous regulation of human mononuclear leucocyte ADP-ribosylation has been identified to be HOCl/N-chloramine production via the oxidative burst of phagocytes. HOCl/N-chloramines are potent oxidants of thiol-containing proteins. Quantitative estimation of N-chloramine sensitive plasma thiols has been identified as an effective surrogate measure of leucocyte poly ADPRT.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Molecular Ecogenetics, University of Lund, Sweden.
R W
RW
Pero
A
A
Olsson
Y
Y
Sheng
J
J
Hua
C
C
Möller
E
E
Kjellén
D
D
Killander
M
M
Marmor
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000532:radiotherapy; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D008787:Metoclopramide / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D009153:Mutagens / Q000633:toxicity; D018384:Oxidative Stress; D011064:Poly Adenosine Diphosphate Ribose / Q000032:analysis / Q000378:metabolism*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000032:analysis / Q000378:metabolism*; D011838:Radiation-Sensitizing Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016335:Zinc Fingers
D000970:Antineoplastic Agents; D009153:Mutagens; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011838:Radiation-Sensitizing Agents; D011064:Poly Adenosine Diphosphate Ribose; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D008787:Metoclopramide