John W. Yarbro

Daunomycin inhibition of DNA and RNA synthesis

Daunomycin is a new antibiotic with antitumor activity against a variety of solid and ascites forms of transplantable animal tumors. It is effective in acute leukemias and certain solid tumors in children. Daunomycin has been considered to inhibit preferentially RNA synthesis, with inhibition of DNA only at higher concentrations, therefore having a biologic mechanism of action similar to actinomycin. The effect of this antibiotic on the 32P incorporation into DNA and RNA of 6C3HD ascites tumor in vitro and in vivo and also on the regenerating mouse liver after partial heptectomy has been studied. These observations indicate that Daunomycin is a more effective inhibitor of the synthesis of DNA than RNA, and hence the biologic mechanism of action of this antibiotic is probably different from that of actinomycin.

Effect of hydroxyurea on regenerating rat liver

Abstract Hydroxyurea has been shown to be a potent inhibitor of DNA synthesis in regenerating rat liver with no measurable effect of RNA synthesis. No detectable difference was noted in incorporation of 14 C-glycine into cytoplasmic protein or into acid-insoluble nuclear protein, but the incorporation into nuclear histone was only 61% of the control value, suggesting that hydroxyurea may inhibit the synthesis of histone in addition to, or as a consequence of, its effect on DNA.

Effect of mithramycin on HeLa cells

Mithramyin is an antibiotic that produces objective improvement in metastatic embryonal cell carcinoma of the testis, hypernephroma and glioblastoma multiforme. Its cytotoxic effect appears to be due to inhibition of RNA synthesis with little or no immediate effect on DNA. Mithramycin was added to tissue cultures of HeLa cells. In low concentrations mithramycin retarded the generation time of cells and at higher concentrations it caused an absolute decrease in the total cell count. The addition of DNA to mithramycin‐treated HeLa cells resulted in significantly less retardation of cell growth. The synthesis of RNA and DNA by the HeLa cells, as measured by the incorporation of 32P, was inhibited after 24 hours of treatment with mithramycin.

Effect of methenolone enanthate (NSC‐64967) in advanced cancer of the breast

Methenolone enanthate, a synthetic long‐acting anabolic steroid, was evaluated by a randomized study in the treatment of advanced carcinoma of the breast in postmenopausal women following the protocol established by the Cooperative Breast Cancer Group. Of 27 patients receiving methenolone enanthate, (48%) had objective improvement. There were no improvements in 13 patients receiving testosterone propionate. The median duration of therapy and the median period of survival from the onset of hormone therapy to death or present living time was greater for the responders to methenolone enanthate than the nonresponders. The unusual high incidence of regression from methenolone enanthate therapy may be due to the massive dose employed, a defect in the method of study being employed in clinical trials, a difference that could occur by chance alone or a difference in the biological nature of the disease in the two groups. Since the difference may indicate that methenolene enanthate is an effective hormone, further studies are warranted.

Effect of urethane, hydroxyurethane and hydroxyurea on synthesis of nucleic acid

The effect of urethane, hydroxyurethane and hydroxyurea on synthesis of nucleic aicd in 6C3HED mouse ascites tumor was measured by incorporation of radiophorus. Hydroxyurethane and hydroxyurea inhibited synthesis of DNA both in vivo and in vitro with little or no inhibition of RNA synthesis except at very high doses. In vitro this inhibition was seen as early as 30 min after addition of the drug. These drugs had an equal capacity to inhibit DNA synthesis in equimolar concentrations. Urethane produced no inhibition of DNA or RNA synthesis in vitro or invivo during the early time periods and at 4 hours in vivo only slight depression of DNA synthesis was noted.

Immunotherapy: The Need for Critical Studies

Excerpt Extensive investigation of the immunology of animal neoplasia suggests that host immunity may be a factor of major importance in host resistance to cancer. Although data from humans provide...

Combination therapy with radiation and mithramycin or actinomycin D in A transplanted mouse glioma

Mouse glioma tumors implanted in C57 black mice were treated with mithramycin or actinomycin D, radiation therapy, and each of these chemical agents in combination with radiation therapy. Response of the tumors to treatment was measured in terms of tumor size, linear growth rate, and survival. Both mithramycin and actimycin D reduced linear growth rate, but survival was not different from the control animals. The antitumor effects of a single course of the chemotherapeutic agents given alone were of relatively short duration. Radiation therapy reduced tumor size, the linear growth rate was less than with the chemotherapies, and survival was prolonged. Actinomycin D or large doses of mithramycin combined with radiation therapy produced a greater reduction of tumor size and linear growth rate than did any of the therapeutic agents alone. Combination therapy was associated with a phenomenon of increased mortality in the early phase of the experiment. There is a suggested enhancement of antitumor activity when these chemotherapeutic agents and radiation therapy are employed in combination.

Effect of Mithramycin on Kidney Transamidinase of C3H Mice

Summary Mithramycin is an antitumor agent known to inhibit the synthesis of RNA and to produce severe renal toxicity. After 3 days of administration of mithramycin to normal mice, there was a significant decrease in kidney transamidinase activities compared to pair-fed control animals. It appears that transamidinase activity is localized in the tubular cells and the loss of enzyme activity is the result of the loss of the integrity of the kidney tubule cells.