B. J. Kennedy

MITHRAMYCIN IN THE TREATMENT OF DISSEMINATED TESTICULAR NEOPLASMS.

DISSEMINATED testicular neoplasms other than seminoma have not been effectively controlled by radiologic therapy or chemotherapeutic agents. In an evaluation of these tumors Whitmore1 stated that chemotherapy had no practical value in most cases because of the brevity or incompleteness of the remissions obtained. There were only 5 effective remissions in 100 treated patients. A recently introduced antibiotic, mithramycin, has demonstrated striking antitumor activity in testicular neoplasms, especially the embryonal-cell carcinoma. Except for seminoma, there is a consistently poor prognosis for testicular neoplasms of germinal origin. Dixon and Moore2 reviewed 990 testicular tumors in the United States Army population from .xa0.xa0.

Mithramycin therapy in advanced testicular neoplasms

Mithramycin is an antibiotic that produces inhibition of the synthesis of RNA in vivo and in vitro. Antitumor activity against germinal neoplasms of the testis has been associated with severe toxicity and a high mortality rate. The study of the synthesis of RNA in an experimental mouse glioma and in mouse liver following treatment with mithramycin revealed a marked dissociation between the rate of recovery of these 2 tissues from the RNA inhibitory effect. Whereas liver rapidly recovered its capacity for RNA synthesis, the recovery of the tumor was delayed. This suggested that an alternate‐day dosage schedule might reduce toxicity while maintaining an antitumor effect in 23 patients with advanced testicular neoplasms treated with an alternate‐day dosage regimen, there was no drug‐induced mortality, drug toxicity was markedly reduced, and antitumor effect was maintained. Therapeutic index of mithramycin has been greatly improved by rational selection of a dosage schedule.

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.

Mediastinal Nonseminomatous Germ Cell Tumors: The Role of Combined Modality Therapy

Twelve male patients with mediastinal nonseminomatous germ cell tumors were treated with chemotherapy (with or without operation and radiation therapy) between 1963 and 1980. Eight patients, treated with only chemotherapy and radiotherapy, died with a median survival from diagnosis of 6 months (range, 3 to 12 months). The 4 survivors remain alive at 12, 15, 34, and 56 months from diagnosis; all are without evidence of disease. All surviving patients were treated with surgical resection of disease either before of after chemotherapy. A major problem in the management of mediastinal nonseminomatous germ cell tumors is the persistence of local disease, which may be overcome by vigorous cytoreductive intervention. Multicenter collaboration will be required to define the optimal combined-modality approach.

Human chorionic gonadotropin and alphafetoprotein in the staging of nonseminomatous testicular cancer

Thirty patients with nonseminomatous testicular cancer and no evidence of metastases outside the retroperitoneum were evaluated for discrepancy between the clinical and pathologic stages and also for frequency of elevations of the serum levels of human chorionic gonadotropin (hCG) and alphafetoprotein (AFP). When marker‐level data were not considered in the staging, the clinical and pathologic stages differed in 47% of the patients; the inclusion of marker data reduced the staging error to 37%. Seven of ten patients with clinical Stage I, pathologic Stage II disease had normal marker levels (false‐negative results). However, there were no false‐positive results: abnormal marker levels before retroperitoneal lymphadenectomy always signalled persistent tumor unless the level could be accounted for by the metabolic decay rate of marker produced by the primary tumor. Comparison of marker‐level data from these patients with data from 48 patients with Stage III disease demonstrated increasing frequency of elevated marker levels with increasing stage (P < 0.001). Serial determinations of HCG and AFP are helpful in clinical staging and are necessary in clinical management.

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.

Breast involvement in acute lymphatic leukemia. Daunorubicine-induced remission; pneumocystis carinii pneumonia

A 15‐year‐old girl had involvement of both breasts with acute lymphoblastic leukemia. Treatment with the combined therapy of daunorubicine, vincristine, and prednisone produced a sustained complete remission of the leukemia. Mammograms demonstrated the concomitant clinical improvement of the breasts. Death was due to pneumocystis carinii pneumonia.

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.

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.