Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase.
The effect of inhibitors of nuclear ADP-ribosyl transferase (ADPRT) on the cytotoxicity of melphalan (L-PAM) in the RIF-1 tumour in vivo was investigated. A large single dose of nicotinamide (1000 mg kg-1) enhanced the tumour cell killing by L-PAM as measured by tumour cell survival. This enhancement was maximum when nicotinamide was administered within 1 h before injecting the L-PAM. When given at this time, the nicotinamide had a dose-modifying effect on all L-PAM doses tested, giving rise to a mean enhancement ratio (ER) of 2.2. Nicotinamide did not appear to inhibit the recovery from L-PAM induced potentially lethal damage. L-PAM (6 mg kg-1) produced a transient drop in mouse body temperature. This effect was both increased and prolonged by nicotinamide. In addition the inhibitor also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 41 min to 143 min. The effect of combining L-PAM with nicotinamide doses below 1000 mg kg-1 was also investigated. The results showed that as the nicotinamide dose was decreased, the enhancement of the effects on body temperature, pharmacokinetics and white blood cell counts were reduced. However, a concomitant loss in the enhancement of tumour cell killing was also observed. Similar results were obtained using 3-aminobenzamide, a more efficient inhibitor of ADPRT.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides / Q000627:therapeutic use; D001831:Body Temperature / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D007958:Leukocyte Count / Q000187:drug effects; D008558:Melphalan / Q000627:therapeutic use*; D051379:Mice; D008809:Mice, Inbred C3H; D009536:Niacinamide / Q000627:therapeutic use; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D011065:Poly(ADP-ribose) Polymerases; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D013997:Time Factors
D001549:Benzamides; D009536:Niacinamide; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases; D009713:Nucleotidyltransferases; D008558:Melphalan