Glynn P. Wheeler

Comparison of the properties of metabolites of CCNU

Abstract Properties of the six isomeric N -(2-chloroethyl- N ′-(hydroxycyclohexyl- N -nitrosoureas, which have been identified by other investigators as metabolites of N -(2-chloroethyl- N ′-cyclohexyl- N -nitrosourea (CCNU), have been compared with those of CCNU and 2-[[[(2-chloroethyl)nitrosoamino]-carbonyl]amino]-2-deoxy- D -glucose (chlorozotocin). There are significant differences in the physicochemical, chemical, and biological properties of these metabolites, and the properties of some of them are significantly different from those of CCNU and chlorozotocin. The position of the hydroxy group and the steric configuration of the compound markedly affect the alkylating and carbamoylating activities of the compounds. The metabolites having the higher alkylating activities and the lower carbamoylating activities produce lethal toxicity to mice at lower molar doses but have somewhat better therapeutic indexes. The data are consistent with the hypothesis that the biological effects observed following the administration of CCNU are due to a large extent to the major metabolites with lesser effects contributed by the minor metabolites. Some of the metabolites have slightly better therapeutic indexes against murine leukemia L1210 than CCNU and chlorozotocin, and they are more soluble in water than CCNU but are active against both intraperitoneally implanted and intracerebrally implanted L1210 leukemia. There might be some therapeutic advantage to administering one of the minor metabolites instead of CCNU or chlorozotocin to cancer-bearing animals.

Studies with mustards. III. In vivo fixation of C14 from nitrogen mustard-C14H3 in nucleic acid fractions of animal tissues

Abstract Experimental evidence is presented which strongly suggests that C 14 from injected nitrogen mustard-C 14 H 3 is fixed in the nucleic acid fractions of animal tissues chiefly as a result of the combination of the nitrogen mustard with nucleic acid moieties. The specific activity of the RNA purine fraction was consistently higher than that of any other nucleic acid fraction examined.

The Cell Cycle of Leukemia L1210 Cells in vivo and in vitro.

Summary The cell cycles of Leukemia L1210 cells proliferating in mice after serial transplantation, proliferating in mice following inoculation of cultured cells, and proliferating in vitro in spinner cultures have been examined by the method of waves of labeled mitoses following pulse exposure to thymidine-(methyl-3H). The cycles for the 3 groups of cells were essentially the same. The following mean values were obtained: TC, 15.7 hr; TG2, 1.5 hr; TM, 0.5 hr; Ts, 11.7 hr; TG1, 2.0 hr.

Prevention of the inhibitory effects of urethan, formamide, and N-methylformamide on the growth of Escherichia coli

Abstract Purines, pyrimidines, ribonucleosides, ribonucleotides, carboxylic acids, and amino acids were tested for activity in preventing the growth-inhibition of Escherichia coli by urethan, formamide and N-methylformamide. 2: 6-Diaminopurine and phenylalanine were the only compounds tested that caused true reversal of the inhibition of growth of E. coli 9637 by these agents, but neither of these compounds rereversed the inhibition of a purine-requiring mutant or, in experiments with urethan, the inhibition of a pyrimidine-requiring mutant. On the other hand, glutamic acid caused true reversal of the inhibition of the purine-requiring mutant and, in experiments with urethan, of the inhibition of the pyrimidine-requiring mutant, but the apparent reversal of the inhibition of E. coli 9637 by glutamic acid was found to be due to stimulation of the overgrowth of drug-resistant mutants. A number of other compounds also stimulated the overgrowth of drug-resistant mutants in overnight growth experiments. Urethan, formamide and N-methylformamide, individually, inhibited the formation of diazotizable amine by resting E. coli B96 cells. The inhibition by urethan was partially prevented by phenylalanine; the inhibition by formamide was partially prevented by glutamic acid and by 2: 6-diaminopurine; and the inhibition by N-methylformamide was partially prevented by 2: 6-diaminopurine. The data indicate that there are probably multiple sites of action for each of these inhibitors.

Chemical properties and biological effects of 2-haloethyl sulfonates☆

Data for the alkylating activities, DNA cross-linking activities, and proliferation-inhibitory activities toward cultured L1210 cells for twenty-four 2-haloethyl sulfonates are reported. Previously reported activities against P388 leukemia in vivo are also presented to permit correlation of in vitro and in vivo properties. Since these compounds are believed to be 2-haloethylating agents, their properties and effects were compared with those of chlorozotocin, which is a recognized 2-chloroethylating agent. 2-Chloroethyl chloromethanesulfonate, which was the most effective compound against P388 leukemia, had a moderate level of alkylating activity and a low level of cross-linking activity, but it was quite active in inhibiting proliferation of cultured L1210 cells. Although its alkylating activity was about the same as that of chlorozotocin, it caused much less cross-linking of DNA. The in vitro tests were useful for gaining information relating structure to the individual properties, but results obtained for one of the properties might not be predictive of the relative values obtained for other properties nor for in vivo activity against P388 leukemia. These results indicate that additional experiments to define the mechanism of action of these agents are needed.

Studies with mustards. Iv. Effects of nitrogen mustard treatment of deoxyribonuclease and deoxyribonucleic acid upon the enzymic degradation of deoxyribonucleic acid.

Abstract Treatment of either deoxyribonuclease or deoxyribonucleic acid with nitrogen mustard caused a decrease in the rate of enzymic degradation of deoxyribonucleic acid, and the treatment of the nucleic acid caused a greater decrease than treatment of the enzyme. The significance of this finding is discussed.

Mechanisms of Action of Anticancer Antibiotics

Perhaps at the beginningof this discussion we should give reasons why we are interested in knowing the mechanisms of action of these antibiotics. On the one hand we are interested for purely academic reasons, that is, to satisfy man’s inquisitive nature and to add to his storehouse of knowledge. This inquisitiveness leads us to ask such questions as the following: Why is a material that is produced by one organism toxic to another organism? Can these toxic effects be prevented or overcome? Are the various toxic materials toxic for the same reason? Why are some organisms not affected by these agents while other organisms are killed by them? Why are some tissues or cells within an organism affected by the agents while other tissues and cells are not? How do organisms become resistant to an initially toxic agent?