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We used the recently described rat popliteal node assay, a sensitive in vivotest of thymic-dependent lymphocyte funciton, to measure the effects of cis-platinum (II) diamminedichloride and gallium nitrate on the ability of spleen cells from treated parental rats to induce a graft-versus-host reaction in hybrid recipients. In doses sufficient to cause morbidity and weight loss of the donor rats, no significant suppression of the reaction could be demonstrated.

Yoshi-864 extends markedly the survival times of mice bearing L1210 leukemia or Ehrlich ascites carcinoma. Busulfan, with methanesulfonate leaving groups identical with those of Yoshi-864, is without effect. Tumor cells from mice bearing the Ehrlich tumor and treated with Yoshi-864 have a persistent reduction in ability to synthesize DNA. Synthesis of DNA in cells from mice treated with busulfan is moderately suppressed at 48 hr after treatment, but returns virtually to the control value at 72 hr.

cis-Dichlorodiammineplatinum (II) (cis-[Pt(NH3)2Cl2]0) is a potent and probably irreversible inhibitor of deoxyribonucleic acid synthesis in cultures of human lymphocytes stimulated with phytohemagglutinin mitogen. At low concentration (3 × 10-6M), selectivity for this process is quite evident; rates of synthesis of ribonucleic acid and protein are only slightly diminished. No resolvable cytologic lesion coincident with the action of the inhibitor was observed by electron microscopy. It was proposed that cis-[Pt(NH3)2Cl2]0may undergo two sequential transformations, with the loss of one Cl-ion at each step, and that the resultant platinum species may act bifunctionally to cross-link adjacent nucleophilic centers through covalent binding.

Dichloro (4,5–dimethyl–o–phenyl–enediamine–N,N′)platinum (II) (DDPP) was synthesized by the reaction of 4,5–dimethyl–o–phenylenediamine with potassium tetrachlo–roplatinate. The resulting compound extended up to 176% the survival times of BALB/c mice bearing the Ehrlich ascites tumor and up to 74% the survival times of BDF1mice bearing the L1210 leukemia. In studies using Ehrlich ascites tumor cells in vitro, DDPP was found to be a potent inhibitor of synthesis of DNA, RNA, and protein; the concentrations which conferred 50% inhibition following 1.5 hr of incubation with the compound were 3 × 10-5to 5 × 10-5M. Inhibition of nucleic acid and protein synthesis in vitro, once established, was not ameliorated by washing the cells with fresh medium devoid of DDPP. Cellular DNA, RNA, and protein, each appropriately labeled with a radioisotopically labeled precursor, became more acid–soluble upon incubation of the cells in vitrowith DDPP. The rate of loss of viability of cells incubated in vitrowith DDPP, as assessed by the trypan blue exclusion method, was found to be considerably greater than the rate obtained upon incubation of cells with an equivalent concentration of cis–dichlorodiammineplatinum(II).

The photochemical reaction product of ammonium hexachloroiridate(IV) retards the rate of development of the Ehrlich ascites carcinoma in BALB/c mice and, to a lesser degree, the development of the L1210 leukemia in BDF1mice. Of the various dos age regimens examined, a maximum of 140% increase of mean survival time was obtained with mice bearing the Ehrlich carcinoma, but only a 20% increase was demonstrated with mice bearing the L1210 leukemia. Blastogenic transformation of phytohemagglutinin-stimulated human lymphocytes in culture was also inhibited by the product, as evidenced by a reduced rate of incorporation of thymidine into cultured cells. No evidence was obtained that the product was a selective inhibitor of deoxyribonucleic acid synthesis; rates of ribonucleic acid and protein synthesis were inhibited to the same extent as the rate of deoxyribonucleic acid synthesis in both cultured human lymphocytes and Ehrlich ascites carcinoma cells in vitro.

1-Hydroxybiuret (1-HB) and 3-hydroxybiuret (3-HB) were shown to be inhibitors of DNA synthesis in an in vitroEhrlich ascites tumor test system in NCTC-109 medium. Inhibition was manifest almost immediately upon addition of either compound to the cells. The rates of synthesis of RNA and protein were not substantially altered by either compound. Removal of each inhibitor by washing the cells did not completely restore the rate of DNA synthesis to its control value. The inhibitory action of each against DNA synthesis was antagonized by a mixture of deoxyribosides, suggesting that inhibition of ribonucleotide bioreduction may be a major mode of action, similar to that of hydroxyurea. Morphological evidence indicated that 3-HB induced unbalanced growth in several strains of Pseudomonas,but 1-HB was devoid of activity in the microbial system.

Gale, GlenR. (Veterans Administration Hospital, Durham, N.C.). Urease activity and antibiotic sensitivity of bacteria. J. Bacteriol. 91:499–506. 1966.—An investigation was made of the responses of certain urease-positive bacteria to various antibacterial drugs in the presence of highly specific urease inhibitors, in a test of the hypothesis proposed by other workers that inhibition of bacterial urease enhances the sensitivity of the cells to antimicrobial agents. Urease inhibitors employed were seven hydroxamic acids (HA). Six of the seven HA reduced the sensitivity of nine Proteusstrains to ampicillin and methenamine mandelate. Two HA increased the sensitivity to colistin, and six HA increased the sensitivity to kanamycin. Investigation of the mechanism of action of the synergistic effect between kanamycin and HA led to the tentative conclusion that potentiation was mediated through an initial alteration of cell permeability by the aminoglycoside antibiotic which permitted accumulation of each of the six HA into the cell, at which point each interacted with pyridoxal phosphate. The single HA which failed to yield synergism with kanamycin failed to interact with pyridoxal phosphate in a nonenzymatic system; the other six HA produced alterations of the normal ultraviolet absorption spectrum of the coenzyme.

Gale, GlenR. (Veterans Administration Hospital, Durham, N.C.) and Helen H. McLain. Effect of ethambutol on cytology of Mycobacterium smegmatis. J. Bacteriol. 86:749–756. 1963.—Electron microscopy showed the effects of the antimycobacterial drug, ethambutol [d-2,2′-(ethylenediimino)-di-1-butanol], on the cytology of Mycobacterium smegmatis. After 10 hr of exposure to the drug, cells no longer contained material which, in control cells, was closely associated with cellular division, possibly genetic substance. No marked changes were observed in other cellular structures. It was concluded that the drug may block one or more steps in the synthesis of pentose nucleic acid or deoxypentose nucleic acid, ultimately causing cessation of cellular division and loss of viability. These cytological findings were compatible with results of other investigators on the mode of action of this drug.