Tissue distribution and biotransformation of potassium oxonate after oral administration of a novel antitumor agent (drug combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate) to rats.

S-1, a new oral 5-fluorouracil (5-FU)-derivative antitumor agent, is composed of tegafur, 5-chloro-2,4-dihydropyridine, and potassium oxonate (Oxo). Oxo, which inhibits the phosphorylation of 5-FU, is added to reduce the gastrointestinal (GI) toxicity of the agent. In this study, we investigated the tissue distribution and the metabolic fate of Oxo in rats after oral administration of S-1. Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU, but little distributed to other tissues, including tumorous ones in which 5-FU was observed after oral administration of S-1. Plasma concentration-time profiles of Oxo and its metabolites after i.v. and oral administration of S-1 revealed that Oxo was mainly converted to cyanuric acid in the GI tract. Furthermore, the analysis of drug-related radioactivity in GI contents and in vitro studies suggested that Oxo was converted to cyanuric acid by two routes, the first being direct conversion by the gut flora in the cecum, and the second, conversion by xanthine oxidase or perhaps by aldehyde oxidase after degradation to 5-azauracil (5-AZU) by the gastric acid. These results indicate that, although a part of the administered Oxo was degraded in the GI tract, Oxo was mainly distributed to the intracellular sites of the small intestines in a much higher concentration than 5-FU and that little was distributed to other tissues, including tumors. We conclude that this is the reason why Oxo suppresses the GI toxicity of 5-FU without affecting its antitumor activity.

[Local chemotherapy by a sustained-release preparation with fibrin seal against the operative wound in head and neck cancer].

Fibrin seal has been used for hemostasis and sealing in operative field of tumors in the head and neck. The authors applied it for drug preparation and tried a local chemotherapy to treat residual and disseminated tumors of cellular level in the operative wound using 5-FU. The drug release rate in this therapy in vitro study was 50% after 24 hrs. When injected to rats bearing Yoshida sarcoma, it exhibited a marked antitumor effect compared to the control group given 5-FU alone. This therapy is easy to make the dosage adjustment and can apply drugs directly to the tumor residue at the high concentration. It will be clinically a useful adjuvant therapy for radiotherapy, surgery or chemotherapy.

Changes in folate concentration in Yoshida sarcoma after administration of leucovorin or cisplatin.

Both leucovorin (LV) and cisplatin (cis-dichlorodiammine platinum II, CDDP) act as modulators of 5-fluorouracil (5-FUra) by increasing the intracellular concentration of reduced folate. We measured intracellular folate levels following the administration of LV or cisplatin in tumor-bearing rats to determine the optimal schedules for their use as 5-FUra modulators. Donryu rats were inoculated with Yoshida sarcoma cells on the right flank. Seven days after tumor inoculation, the animals were injected with LV or CDDP. The kinetic and dose-related changes in intracellular folate concentration were analyzed by means of a binding assay. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after administration of LV and remained significantly high until 8 h after administration. Folate levels in the tumor tissues were significantly higher than baseline 1 and 2 h after cisplatin administration, then decreased to a rather low level 8 h after, and to a significantly lower level than baseline 24 h after administration. The folate levels in the tumor tissue increased in proportion to the dose of LV, but did not increase when the dose of cisplatin was increased from 1 mg/kg to 8 mg/kg. Repeat high-dose administration of LV and repeat low-dose administration of cisplatin are advocated when they are used as modulators of 5-FUra.

Field bean protease inhibitor preparations, unlike methotrexate, can completely suppress Yoshida sarcoma tumor in rats.

Protease inhibitor preparations (PIP) with antitryptic and antichymotryptic activities, isolated from field bean legume as well as doxorubicin and cyclophosphamide could effectively suppress the growth of Yoshida sarcoma ascites tumor cells transplanted in adult rats and prevent their death. As against this, methotrexate and heat-inactivated PIP were ineffective in such rats at varied doses of treatment tried. The percent survival of animals appeared to be related to the purity, treatment mode and the dose of PIP used. Zymographic analysis of the trypsin activated sarcoma cell homogenate revealed the presence of six protease bands in the molecular weight range of 51kD to 206kD. Prolonged interactions of such zymograms with protease inhibitors such as 20mM EDTA or 5mM diisopropyl flurophosphate (DIFP) or 400 micrograms/ml of PIP in reaction buffer indicated that these are not metalloproteases but serine proteases whose activities are inhibited by PIP and DIFP. Since proteases are involved in cell growth regulation and cell transformation, we hypothesize a positive relationship between the field bean protease inhibitor's blocking action on tumor cell proteases and its tumor suppressing activity.

[Index of tumor response by in-vivo 31P-MRS--T1 effect as a new predicting index of therapeutic effects].

We observed the metabolism of the Yoshida sarcoma by in-vivo 31P-MRS, using two varieties of repetition time (TR), i.e., TR2s and TR10s. It was measured before the injection of 5FU and 4, 24, 48 hours after the injection. In the each time, PME/ATP ratio, intracellular pH, and TR10/TR2 ratio of PME which reflects the T1 value of PME, were calculated. TR10/TR2 ratio of PME decreased 4 and 24 hours after the injection of 5FU and recovered 48 hours after the injection to the same level before the injection. However decrease of PME/ATP ratio was not observed until 48 hours after the injection of 5FU, when apparent tumor regression appeared. These results suggested that the T1 value of PME decreased prior to the PME changes and when the PME decreased, the intracellular environment of PME recovered to the same state before the therapy. It was considered that the TR10/TR2 ratio of PME offers significant information different from the PME/ATP ratio. It is possible to use the TR10/TR2 ratio as a predicting index for the therapeutic effects.

[Experimental toxicologic and therapeutic studies on the activity of the CMF(cyclophosphamide-methotrexate-5-fluorouracil) scheme versus the VMF(vincristine-methotrexate-5-fluorouracil) scheme]. / Experimentelle toxikologische und therapeutische Untersuchungen zur Wirkung des CMF-(Cyclophosphamid-Methotrexat-5-Fluorouracil)-Schemas gegenüber dem VMF-(Vincristin-Methotrexat-5-Fluorouracil)-Schema.

Experimental administration of the CMF scheme, which is used in adjuvant chemotherapy in humans, resulted in carcinogenic effects in rats. When substituting cyclophosphamide by vincristine, no carcinogenic activity was observed. The therapeutic effect of the VMF scheme was approximately equivalent to that of the CMF scheme in various experimental designs. It is discussed whether in adjuvant chemotherapy combinations should rather be used which lack any long-term toxicity such as carcinogenic effects.

Superadditive cytostatic effects after combined administration of vincristine, bleomycin and methotrexate to Yoshida sarcoma.

Vincristine, bleomycin and methotrexate are three cytostatic drugs which are particularly effective in epidermoid carcinoma of the head and neck region. As their dose-limiting side effects differ from one another, it appeared reasonable to combine them. To examine in vitro whether this combination increases cytostatic activity, the three drugs were administered to Yoshida sarcoma. It could be demonstrated that the growth inhibition activity and the cell disturbance activity were much higher with combination therapy than with single drug therapy. From this, it follows that beneficial results in the treatment of head and neck carcinomas can be expected.

[Tumour inhibitory N-(bis--(2-chlorethyl)-aminomethyl)-urethanes (author's transl)]. / Uber cytostatica. 22. Mitteilung. Tumorhemmende N-Bis-(2-chloräthyl)-aninomethyl]-urethane

The synthesis of N-[bis-(2-chlorethyl)-aminomethyl]-urethanes (I-VI) and N,N'-di[bis-(2-chlorethyl)-aminomethyl]-urea (VII) and their evaluation on the Yoshida sarcoma of the rat and on the sarcoma 180 of the mouse are described. The antitumor activity of I-VI is based on a reaction mechanism analogous to that of aromatic N-lost-derivatives.

Antitumor effect of 2-thio-4-hydrazinouracil on transplantable tumors.

The cytostatic activity of 2-thio-4-hydrazinouracil (THU) on some transplantable tumors has been studied. A strong effect of this compound (between 60% and 100% suppression) has been found in the case of Myeloma P-8 (MOPC-21) and Sarcoma 180 (Crocker). A less pronounced effect has been observed on Yoshida sarcoma, while the development of Jensen sarcoma is not influenced.