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The mode of action of the radiosensitizing analogs metoclopramide and nicotinamide

Olsson, Anders LU (1997)
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... (More)
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. (Less)
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author
opponent
  • Dr. Siemann, Dietmar W, University of Florida, Gainesville, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
medical instrumentation, metoclopramide, nicotinamide, apoptosis, radiosensitization, NAD, benzamide, DNA repair, Clinical physics, tomography, radiology, Klinisk fysiologi, radiologi, tomografi, medicinsk instrumentering
pages
150 pages
publisher
A Olsson, Molecular Ecogenetics, Wallenberg laboratory, Box 7031 220 07 Lund,
defense location
Wallenberglaboratoriet Sölvegatan 33, Lund
defense date
1997-06-04 13:00
external identifiers
  • other:ISRN: LUMEDW/MECM--97/1002--SE
language
English
LU publication?
yes
id
b344633c-dcc0-4164-881b-9bae323202f7 (old id 29329)
date added to LUP
2007-06-12 16:25:30
date last changed
2016-09-19 08:45:15
@phdthesis{b344633c-dcc0-4164-881b-9bae323202f7,
  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;<br/><br>
<br/><br>
• 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.<br/><br>
<br/><br>
• 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.<br/><br>
<br/><br>
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.},
  author       = {Olsson, Anders},
  keyword      = {medical instrumentation,metoclopramide,nicotinamide,apoptosis,radiosensitization,NAD,benzamide,DNA repair,Clinical physics,tomography,radiology,Klinisk fysiologi,radiologi,tomografi,medicinsk instrumentering},
  language     = {eng},
  pages        = {150},
  publisher    = {A Olsson, Molecular Ecogenetics, Wallenberg laboratory, Box 7031 220 07 Lund,},
  school       = {Lund University},
  title        = {The mode of action of the radiosensitizing analogs metoclopramide and nicotinamide},
  year         = {1997},
}