Structure-activity relationships for tumour radiosensitization by analogues of nicotinamide and benzamide.
Nicotinamide has been shown in our laboratory and those of other investigators to be an effective radiosensitizer of a variety of mouse tumours, while producing little or no radiosensitization of normal tissues. Its mechanism of action is different from classical electron-affinic compounds and appears to be the result of improved tumour oxygenation. In this study we have synthesized 29 analogues of nicotinamide and benzamide and characterized them for their tumour radiosensitization and acute toxicity in mice. The data show that a wide range of additions to the nicotinamide and benzamide ring produce tumour radiosensitization similar to that produced by equimolar doses of misonidazole, but that substitutions of the amide tend to reduce radiosensitization. Other structure-activity relationships are evident. Although some compounds produce similar tumour radiosensitization to nicotinamide at equimolar doses, and are comparably low in acute toxicity, none appears sufficiently superior to supplant nicotinamide itself as a candidate for clinical trials. Thus these data provide evidence that nicotinamide, because of the extensive experience with its use in man, is likely to be the best drug in the benzamide-nicotinamide series for development as a radiosensitizer of human tumours.
Brown
J M
JM
Department of Radiation Oncology, Stanford University School of Medicine, CA 94305.
Lemmon
M J
MJ
Horsman
M R
MR
Lee
W W
WW
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use / Q000633:toxicity; D004307:Dose-Response Relationship, Radiation; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000401:mortality / Q000532:radiotherapy*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000627:therapeutic use / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use* / Q000633:toxicity; D013329:Structure-Activity Relationship
D001549:Benzamides; D011838:Radiation-Sensitizing Agents; D009536:Niacinamide