sodium-cyanate and Leukemia-P388

Sodium cyanate is a selective in vivo inhibitor of protein synthesis in a variety of mammalian tumor cells without a corresponding effect on the normal tissues of tumor-bearing animals. The in vivo decrease of protein synthesis observed 4 h post-NaOCN i.p. administration in the murine P388 leukemia cell cannot be explained by decreased amino acid pools in the mouse peritoneal cavity. In addition, the decrease in protein synthesis observed with NaOCN in isolated P388 cells was shown not to be secondary to (a) alterations in the kinetics of amino acid transport or (b) effects on total nucleotide pools. The incorporation of [14C]phenylalanine in P388 cell-free lysates from NaOCN-pretreated mice was significantly decreased to approximately 55% of control lysates in the presence of exogenous amino acids. The addition of exogenous calf liver tRNA to the lysates did not alter this result. However, no difference was observed in polyuridylic acid-directed [14C]phenylalanine incorporation into polypeptides in micrococcal nuclease-treated P388 lysates from NaOCN-pretreated or control mice. Quaternary initiation complex (48S) formation and mRNA synthesis were found to be significantly decreased by 35 and 38%, respectively, in P388 cells from NaOCN-pretreated mice. DNA synthesis was decreased by 66% of control at 1 h and 62% at 4 h post-NaOCN i.p. administration. No apparent effect with NaOCN was observed on total RNA synthesis in P388 cells. These results suggest that the decrease in P388 cell protein synthesis observed with NaOCN in vivo appears to be due to alterations manifested in the synthesis of cellular mRNA and protein synthesis initiation processes. NaOCN does not appear to affect the P388 cell ribosomal machinery, tRNA, or protein synthesis elongation processes.

Topics: Adenosine Triphosphate; Amino Acids; Animals; Cyanates; Cycloheximide; DNA; Leukemia P388; Leukemia, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Neoplasm Proteins; Phenylalanine; RNA, Messenger

Sodium cyanate (NaOCN) at a dose of 250 mg/kg was shown to decrease protein synthesis in P388 leukemia tumor cells to approximately 52% of control values at 2 h and 32% at 5 h after NaOCN administration, without a corresponding decrease in various normal tissues of the tumor-bearing CD2Fl mice. CD2Fl mice that had received P388 tumor cells IP 1 day prior to drug administration underwent various schedules of treatment with NaOCN and melphalan (MLN). NaOCN (200 mg/kg or 250 mg/kg) administered IP has no significant antitumor activity (increased mean lifespan [ILS] less than 20%). The simultaneous IP administration of NaOCN (250 mg/kg) plus MLN (15 mg/kg) resulted in a significantly greater antitumor activity (approximately 265% of control, with 21 of 30 animals being long-term survivors) than MLN (15 mg/kg) alone (approximately 156% of control, with 11 of 30 animals being long-term survivors). This synergism was not observed when MLN was administered 4 h after NaOCN administration. The synergistic activity of MLN with NaOCN does not appear to be secondary to alterations in the absorption from the peritoneal cavity into the systemic circulation as determined by 3H2O. NaOCN does not increase the intracellular concentration of [chloroethyl-14C]MLN into P388 cells. The mechanism of the synergistic antitumor activity of simultaneous IP administration of NaOCN and MLN is unknown.

Topics: Absorption; Animals; Body Water; Cyanates; Drug Interactions; Leukemia P388; Leukemia, Experimental; Life Expectancy; Male; Melphalan; Mice; Mice, Inbred BALB C; Neoplasms, Experimental