Active enhancement of rat cardiac allografts induced by donor specific semisoluble antigens.

Active enhancement was induced in inbred rats with cardiac allografts using semisoluble antigens. The optimal time of antigen pretreatment and optimal dose of semisoluble antigens were examined. The presence of serum blocking factors in the sera of rats having had allografts for a long time was examined with a macrophage migration inhibition test and lymphocyte microcytotoxicity assay. Since the blocking factors of macrophage migration inhibition were increasing on the 7th day, that day was determined to be the optimal time of antigen pretreatment. The mean survival time (MST) of cardiac allografts in untreated rats was 17.2 +/- 7.5 days. Semisoluble antigens were administered at 2 mg/kg body weight 7 days before the graft, 4 mg/kg 7 days before the graft and 2 mg/kg divided over three days, 15, 8 and 1 day before the graft, and the MSTs of cardiac allografts of rats receiving these treatments were 71.2 +/- 39.9, 62.6 +/- 42.2 and 79.3 +/- 31.0 days, respectively. The MST in each group of the treated rats was significantly longer than that of the control group (p less than 0.01). Rejection of the allograft, however, was accelerated in a group treated with 8 mg/kg 7 days before the graft (MST: 8.4 +/- 3.2 days). Serum blocking factors were detected in the sera of approximately half of the rats having cardiac allografts which survived a long time.</p

Antitumor Effects of Natural-Human TNF on BDFI Mice Bearing Lewis Lung Carcinoma

Natural-human tumor necrosis factor (n-TNF) was obtained by isolating and refining lymphokines which were extracted from human acute lymphoblastic leukemia BALL-I cells. Antitumor effects of this n-TNF were studied by using Lewis lung carcinoma (3LL) which was transplanted on BDFI mice. n-TNF showed inhibitory effects of the proliferation of metastatic tumors dose-dependently through i.v. injection daily for 10 days. And the study of the dose schedule of the administration and the route of the administration showed that routes of i.v., i.m. and i.t. injections were effective respectively through daily administration. Histological study showed effects which were ranked Grade Ilb (and partially III) of Shimosato and Ohboshi's histological criteria

Synergistic Antitumor Effects of Natural Human Tumor Necrosis Factor and Mouse Interferon Beta and Gamma

Referring to synergistic antitumor effects of natural human tumor necrosis factor (n-TNF) derived from human acute lymphoblastic leukemia BALL-I cell as well as mouse interferon beta (mIFNbeta) and mouse interferon gamma (mIFNgamma), a series of the study was made using Lewis lung carcinoma grafted on BDF1 mice. With a combination dose of n-TNF (1 x 10^2 U/kg/day) and mIFNbeta (1 x 10^2 IU/kg/day) as well as that of n-TNF (1 x 10^2 U/kg/day) and mIFNgamma (1 x 10^2 IU/kg/day), a significant enhancement of antitumor effect was observed. Furthermore, with a triple combination dose of n-TNF (1 x 10^2 U/kg/day), mIFNbeta (I x 10^2 IU/kg/day) and mIFNgamma (I x 10^2 IU/kg/day), too, a strong synergistic effect was noted. The concentration of n-TNF required for concomitant use with mIFNbeta and mIFNgamma was 1 over 5 x 10^3 of that required for single dose of n-TNF, to obtain the same level of effect

The Synergistic Antitumor Effect of Natural-Human TNF and Anticancer Drugs

In the present report, we compared and discussed synergistic antitumor effects of natural-human tumor necrosis factor (n-TNF) which was derived from human acute lymphoblastic leukemia BALL-I cells and conventional anticancer drugs by using Lewis lung carcinoma which was transplanted on BDF1 mice. n-TNF and anticancer drugs were administered daily for 10 days. n-TNF showed antitumor effects which were equivalent to or stronger than MMC (1 mg/kg/day, i.v.), 5FU (5 mg/kg/day, i.v.), Adriamycin (1 mg/kg/day, i.v.), Actinomycin D (0.05 mg/kg/day, i.v.), Cyclophosphamide (10 mg/kg/day, i.v.) and OK-432 (0.5 KE/mouse/day, s.c.). And synergistic antitumor effects were observed when n-TNF was administered with anticancer drugs, and the strong enforcement was obtained especially when it was combined with 5FU

Synergistic Antiproliferative Effects of the Combination of Natural Human Tumor Necrosis Factor-&#945; and Natural Murine Interferon-&#945;/&#946; against Colon-26 Adenocarcinoma Hepatic Metastases in a Murine Model

To prevent the development of hepatic metastases after surgery for colorectal cancer, it is important to inhibit the growth of any micrometastases which occur during the operation. We used a hepatic metastasis model in mice to investigate the effects of combination therapy with natural human tumor necrosis factor-alpha (nHuTNF-alpha) and natural murine interferon-alpha/beta (nMuIFN-alpha/beta). Decreased formation of hepatic metastases by murine colon-26 carcinoma was recognized following a single injection of nHuTNF-alpha, nMuIFN-alpha/beta, or both. These inhibitory effects were synergistic. NK activity was also measured, because notaral lerller cells not only have an anti-tumor effect but are also a representative of the host immune system. Both nHuTNF-alpha and nMuIFN-alpha/beta were able to activate NK cells, and the combination of the cytokines more significantly augmented NK activity. The in vivo elevation of NK activity induced by nHuTNF-alpha, nMuIFN-alpha/beta, or their combination may be one of the mechanisms of their antiproliferative effect on experimental hepatic metastases of murine colon-26 carcinoma.</p

Antitumor effect of natural human tumor necrosis factor-beta against Lewis lung carcinoma in mice and its synergistic potentiation by interferon.

We investigated the antitumor effect of purified natural human tumor necrosis factor-beta (nHuTNF-beta) produced by human acute lymphoblastic leukemia BALL-1 cells stimulated with HVJ on pulmonary metastatic tumors of Lewis lung carcinoma (3LL) transplanted into BDF1 mice. nHuTNF-beta showed antiproliferative effects on metastatic tumors in a dose-dependent manner when administered daily for 10 days by the intravenous route. Histological examination of the tumors treated with nHuTNF-beta revealed that the tumor size and number of metastases were much reduced. Lytic cellular changes, including cytoplasmic vacuolation, loosening of the intercellular junction and both cytoplasmic and nuclear swelling, were found, but tumor necrosis was not. These findings indicate a therapeutic effect of Grade IIa according to the histological criteria of Shimosato and Ohboshi. In addition, synergistic augmentation of the antiproliferative effects of nHuTNF-beta by natural murine interferon-alpha/beta (nMu-IFN-alpha/beta) or recombinant murine interferon-gamma (rMuIFN-gamma) was recognized by median effect plot analysis. The results suggested that nHuTNF-beta may well deserve clinical trial as a new immunotherapeutical agent for human cancer.</p

Effect of selected splenic irradiation on growth of meth A-fibrosarcoma in mice and partial characterization of splenic effector and suppressor cell populations.

Meth A-fibrosarcoma bearing BALB/c mice were subjected to selected splenic irradiation (2.0-4.0 Gy) on days 7 and 14 of tumor growth. Tumor growth was recorded by serial measurement. Irradiation given on day 7 caused regression of tumor, but irradiation given on day 14 did not show tumor regression. Antitumor activity in the Winn assay was detected in spleen cells 3 days after irradiation, but was not detected 7 days after. The cell surface phenotypes were analyzed on days 3, 7 and 14 of splenic irradiation using monoclonal antibodies (anti-Thy1.2 antibody, anti-Lyt1 antibody, anti-Lyt2 antibody, anti-L3T4 antibody) by flow cytometry. Thy 1.2, Lyt1, and L3T4 cells were increased on day 3 of splenic irradiation, but were not on days 7 and 14. Lyt2-cells did not show increase on days 3, 7 and 14. It was possibly suggested that selected splenic irradiation induced tumor regression was caused by the ability of irradiation to preferentially eliminate suppressor T cells, thereby allowing effector T-cells to become relatively dominant.</p

Comparison of the Subrenal Capsule Assay and Succinate Dehydrogenase Inhibition Test as Drug Sensitivity Tests for Cancer

The same chemotherapeutic agents were tested against fresh surgical explants of solid tumors obtained from 50 patients using the in vivo subrenal capsule (SRC) assay and the in vitro succinate dehydrogenase inhibition (SDI) test in comparison. Control growth adequate to meet evaluable assay criteria was obtained in 36 of the 50 tumors tested in the SRC assay (72.0%). In the SDI test, 46 of 50 tumors were evaluable (92.0%). Correlations between the two test systems were dependent upon the activity criteria established for each system. With activity criteria set at a change of less than or equal to -2.0 in the drug sensitivity score for the SRC assay and greater than or equal to 50.0% inhibition of succinate dehydrogenase activity for the SDI test, 12.5% of the drugs tested were active in the SRC assay and 22.3% were active in the SDI test. Correlations of tumor response between the two test systems were 31.7% for sensitivity (13/41) and 95.1% for resistance (98/103). In spite of the fundamental difference between the SRC assay and SDI test, meaningful correlations between the test results and clinical tumor responses in both test systems were obtained. This fact suggests that the two methods are complementary to each other.</p

The Clinical Significance of CT in the Preoperative Diagnosis of Colon and Rectal Cancer

The clinical significance of CT in the preoperative diagnosis of colon and rectal cancer was studied. Thirty four patients were investigated in this series. The diagnostic criteria of the CT examination were previously established in a study of wall invasion (S factor), lymph node metastasis (N factor), liver metastasis (H factor) and peritoneal dissemination (P factor). The CT diagnosis was done prospectively according to these criteria, and the CT diagnosis was compared with the macroscopic and histological diagnosis. The accuracy of the prospective diagnosis as to H, S, N and P factors was 79.4%, 55.9%, 41.2% and 20.6%, respectively. The diagnostic value of CT seemed to be acceptable as to the H factor, but limited to some extent to the S and N factors

Early diagnosis of acute renal allograft rejection: efficacy of macrophage migration inhibition test as an immunological diagnosis

1. Three cases of acute rejection were detected by macrophage migration inhibition tests (MIT) conducted directly on seven patients who had received renal allografts. The macrophage migration inhibitory factor (MIF) activity was positive in all cases 1-2 days before the appearance of acute rejection. 2. After the administration of a high dose of Solu-Medrol (1g/day for 3 days) to suppress the acute rejection, MIF activity recovered to its normal level 3 days later. These findings seem to indicate that MIT yields immunologically useful criteria for the early detection of an acute rejection.</p