The mode of action of the radiosensitizing analogs metoclopramide and nicotinamide

University dissertation from A Olsson, Molecular Ecogenetics, Wallenberg laboratory, Box 7031 220 07 Lund

Abstract: This thesis provides the first attempt to study the nicotinamides and benzamides from a mode of action point of veiw. Understanding the effects on DNA repair, cell cycle control (proliferation) and cell death from these agents and in combination with ionizing radiation, provides a new opportunity to logically develop better approaches to sensitize already existing therapies via for example induction of apoptosis or inhibition of DNA repair. Metoclopramide (MCA) and nicotinamide (NAM) have both been shown to possess radiosensitizing properties. Their mode of action however seems to be quite different; • MCA, a N-substituted benzamide; (i) Radiation induced DNA damage was sensitized by MCA in vivo when evaluated using three different methods, namely; alkaline elution, nucleoid sedimentation and measurements of the NAD pools, (ii) MCA sensitize low dose radiation in two different tumors; a human lung adeno carcinoma and a mouse sarcoma, carried by scid and CBA mice, respectively, (iii) MCA per se induces DNA damage, induces apoptosis, inhibits cell proliferation and clonogenicity in vitro in HL-60 cells and has a direct antitumor effect in vivo. • NAM, a non-N-substituted benzamide analog; It was shown to have effects on (i) tumor vascularization, (ii) DNA repair, (iii) poly(ADP-ribosyl)polymerase (PARP) inhibition, (iv) DNA damage, and (v) energy metabolism. In addition, by conformationally altering the formulations of MCA by pH adjustment, neutral MCA has become safer with less side effects without affecting its bioavailability and sensitizing properties. In conclusion, the N-substituted benzamide analogs are distinguished from the non-N-substituted analogs because they are susceptible to radiolysis, induce cytotoxicity by apoptosis, inhibit cell proliferation and clonogenic growth, activate PARP and have no effect on microregional tumor blood perfusion.

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