Ruboxyl, a new nitroxyl derivative of daunorubicin - acute toxicity and antitumor effect in animals.

Ruboxyl (RBX), a new nitroxyl derivative anthracycline, showed an interesting cytotoxic effect on in vitro established human cell lines and an antitumor activity in tumor-bearing animals. In this study, we further investigated the antitumor effect of this drug compared to Doxorubicin (DX) in four in vivo systems of experimental murine tumors. Our data demonstrate that RBX had little effect on the growth of primary tumor, and on the survival, in mice bearing Lewis lung carcinoma (3LL), while the drug showed a higher effect on the growth of B 16 melanoma. In both the experimental murine systems the activity of RBX was similar to that exerted by DX. As regards the leukemia models, RBX induced a significant increase on survival in mice bearing both L1210 or L5178Y leukemias. However, the effect on survival and the number of long-term survivors (LTS) were lower than that observed following DX treatment.

Potential anticancer agents--nitroxyl derivatives of Rubomycin.

Two new of the spin-labeled analogues of Rubomycin were studied. It was shown that spin-labeled derivatives were less toxic than the parent compound and had a broad-spectrum antitumor activity. Spin-labeled derivative was clearly less cardiotoxic in the rat model than Rubomycin (Daunorubomycin).

Radiosensitizer AK-2123 as modulating agent in the chemotherapy of experimental metastases.

Therapeutic effect of Cyclophosphamide (CPA) and radiosensitizer AK-2123 (AK) combination versus CPA alone in the same doses was investigated on transplanted LL carcinoma and B 16 melanoma. Antimetastatic efficacy of different doses of CPA and combined therapy was evaluated. Our data demonstrate that the effect of combined treatment by CPA at low uneffective doses (60 mg/kg, 40 mg/kg, 20 mg/kg at the 3rd and the 7th day after transplantation) and AK at low daily doses (1 mg/kg and 0.1 mg/kg for 3-9 days after transplantation) is equal or superior to the effect of CPA alone at the therapeutic dose (120 mg/kg).

Modulatory effect of tempol on toxicity and antitumor activity of 6-mercaptopurine and on P450 cytochrome level.

Low selectivity of contemporary antitumor drugs requires a search for its improvement. In this context, nitroxyl radicals are of interest as promising pharmacological agents. The introduction of nitroxyl radical into the structure of antitumor cytostatics was found to reduce considerably their general and specific toxicity. In this work, we demonstrate a detoxifying effect of tempol upon its combined injection with cytostatics at their absolute lethal dose in the intact mice as well as an improvement of sensitivity of tumor-bearing animals to 6-MP. Tempol is shown to normalize the level of oxidized form of P450 cytochrome in a liver, reduced as a result of the injection of 6-MP.

Subrenal capsule assay of human tumor chemosensitivity.

Breast and colon tumor response to emoxyl, a nitroxyl derivative of daunomycin, was detected using human tumor heterotransplantation under the renal capsule of immunocompetent mice. The substitution of adriamycin by emoxyl in the combined therapy led to enhanced therapeutic efficacy. The evidence of enhanced response of breast tumors to emoxyl obtained during the histologic examination of xenografts is in good agreement with measurements of tumor fragment weight. It is suggested to use a quantitative kinetic index kappa calculated by the method of equivalent exponents for objective evaluation of tumor response to the drugs.

Pharmacokinetics of a spin-labeled rubomycin analog.

Pharmacokinetics of a spin-labeled analog of rubomycin (ruboxyl) was studied. Differences were found in ruboxyl pharmacokinetics in normal and tumor-bearing animals. Most of the drug was excreted within 6 h. The differences in pharmacokinetics of ruboxyl and nitroxyl radical were established.

Comparative in vitro and in vivo study of a nitroxyl derivative of 5-fluorouracil (magnizil) on human gastrointestinal tumors.

AIMS AND BACKGROUND: There is much interest in nitroxyl derivatives of cytotoxic agents. We evaluated the potential activity of magnizil, a derivative of 5-fluorouracil, on human gastrointestinal tumors in 3 different in vitro and in vivo experimental models. METHODS: The activities of magnizil and 5-fluorouracil were comparatively determined in vitro on the HT29 cell line by a clonogenic assay and on tumor clinical specimens by an antimetabolic assay. The activity of both the drugs against human tumors was also assessed in mice with the subrenal capsule assay. RESULTS: A similar cytotoxic activity was found for magnizil and 5-fluorouracil on the HT29 cell line. As regards human tumors, a lower activity was observed for the nitroxyl derivative than for 5-fluorouracil, with response rates of 25% and 50%, respectively, at comparable concentrations. Moreover, among the tumors transplanted in the subrenal capsule of mice, two were sensitive to magnizil and 3 to 5-fluorouracil. CONCLUSIONS: Even though experimental results on human tumors indicate a somewhat lower activity for magnizil than the parent compound, its low toxicity and the possibility to clinically use high doses suggest the opportunity to further investigate the potential of this new anticancer agent on larger series of colorectal cancers in experimental systems.

Nitroxyl radicals decrease toxicity of cytostatic agents.

Nitroxyl radicals of a series of piperidineoxyles and pirrolinoxyles increase the tolerance of experimental animals to the injection of otherwise lethal doses of anti-tumor cytostatic agents. Simultaneous injection of nitroxyl radicals in different doses with 6-mercaptopurine, thiophosphamide, cyclophosphamide and the other cytostatic agents results in decreased toxicity and survival of animals. Nitroxyl radicals normalize the level of the oxidized form of P450 cytochrome that is decreased by the injection of lethal doses of cytostatic agents.