[Role of host immunity in experimental radiotherapy].
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Biomedical subjects
Publications and source records attributed to Y Hanatani.
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The effects of cyclophosphamide (CPA) and its active form, 4-hydroperoxy-CPA, against human breast carcinoma transplanted into nude mice (BALB/c nu/nu) were evaluated in terms of the decreases of hepatic drug-metabolizing enzymes in nude mice. A human breast carcinoma, MX-1, was implanted into the subcutaneous tissue of nude mice and a drug was administered intravenously once at a dose of 0.05, 0.1 or 0.15 mmol/kg, 1 or 3 weeks after tumor inoculation. 4-Hydroperoxy-CPA was more effective than CPA as regards inhibition of tumor growth, and the difference in effect was greater when the drugs were administered 3 weeks after tumor inoculation. The activity of CPA was depressed by the decrease of the hepatic drug-metabolizing enzymes in proportion to the tumor-bearing period. Therefore, the effects of masked derivatives of CPA may correlate with the changes in drug-metabolizing activities of tumor-bearing mice. The human tumor xenografts-nude mice system is considered to be suitable for chemosensitivity tests with masked compounds.
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Three human gastric carcinomas and one colon carcinoma serially transplanted to nude mice were used for experimental chemotherapy of mitomycin C (MMC) with special reference to the start of drug administration. BALB/c nu/nu male originated from the Central Institute for Experimental Animals were used. All the experiments were carried out under the specific pathogen-free conditions using laminar air flow racks. Tumors used for experiments were St-4; poorly differentiated adenocarcinoma of stomach, St-15; mucinous adenocarcinoma of stomach, KS-1; poorly differentiated adenocarcinoma of colon. MMC at the doses of 2 or 3 mg/kg were administered intraperiatoneally once a week for 3 or 4 times starting from 24 hours (DAY-1 Adm.) or 2 weeks (DAY-14 Adm.) after tumor inoculation. Response to chemotherapy was evaluated on the basis of growth curves, tumor weights, and histopathological changes. Whereas St-15, a sensitive strain to MMC, was suppressed by DAY-1 and DAY-14 administration. Similarly, DAY-1 administration revealed more excellent effect on the other three tumors than DAY-14 administration. These results indicated that MMC was more effective when the tumor mass was smaller, and also suggested that the adjuvant chemotherapy of surgical operation should be started as soon as possible after tumor resection or reduction. In the case of DAY-1 treatment, the false positive result by anti-vascularization effect of MMC could not be excluded, it seems to be adequate that drug administration should be started after the initiation of logarithmic growth phase of the tumors.
The activities of hepatic microsomal drug-metabolizing enzymes in nude mice (BALB/c-nu/nu) bearing tumors of human or nude mouse origin were studied. The content of cytochrome P-450 and the activities of cyclophosphamide oxidase, benzo[a]pyrene hydroxylase, aniline hydroxylase and benzphetamine N-demethylase were markedly decreased in tumor-bearing nude mice in accordance with previous observations in tumor-bearing rats and mice. These results indicate that decreases in the activities of hepatic microsomal drug-metabolizing enzymes are not the consequence of an immunoreactive process or cachexia.
Microangiographic study was performed with ten human tumors serially transplanted into nude mice to clarify the role of tumor vessels on the chemosensitivity of the human tumors. Five gastric carcinomas, two colon carcinomas, one breast carcinoma, one cholangiocarcinoma, and one hemangiopericytoma were used for the experiments. Seven tumors revealed hypervascular network of vessels, whereas hypovascular patterns of tumor vessels were observed in the other three tumors. It was found that the histologically differentiated tumors were hypervascular and undifferentiated tumors were hypovascular, with statistically significant differences (p less than 0.05). Each tumor possessed the vascular network similar to human tumors originated from the same organs. No discernible changes of microangiographic features were noticed by serial transfers. As the chemosensitivities of these tumors depended mainly on their original tissues, these chemosensitivities could not be explained only by tumor vascularities or drug transferences. However, in the tumors with similar chemosensitive spectra, less susceptible tumors were observed to possess the irregular vascular networks in comparison with sensitive strains. From these considerations, tumor vessels were thought to have some role on vascular flow and drug transference which affected chemosensitivity of human tumors.
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Collagen gel droplet embedded culture drug sensitivity test (CD-DST) was applied to 33 patients with gastric cancer (30 primary tumors, 12 metastatic tumors and 25 biopsy specimens). Evaluable rates by CD-DST were 80% for primary tumors, 75% for metastatic tumors and 72% for biopsy specimens. Chemosensitivities of primary tumors were: 5-fluorouracil 25%, mitomycin C 17%, cisplatin 13%, adriamycin 17%, etoposide 21%. Chemosensitivities of metastatic tumors were lower than those of primary tumors. In 4 out of 6 patients who had measurable lesions, clinical responses to chemotherapy were predictable by CD-DST.