Effects of conjugated and nonconjugated antithymocyte globulin and trenimon on T lymphocytes and skin graft rejection.

These studies were undertaken to investigate the use of a technique for "homing" of an alkylating agent to lymphocytes as an immunosuppressive approach to inhibit allograft rejection. Trenimon (Tr) was bound covalently to antithymocyte globulin (ATG) and the effects of the complex on peripheral blood cells, thymus cells, spleen cells, and on foreign skin graft rejection assessed. When rabbit ATG was bound covalently to Tr, an alkylating agent, the conjugate (ATG-Tr) retained both complement-dependent antithymus cell acitivity and alkylating activity in vitro, but these activities were reduced. In vivo ATG decreased lymphocytes and increased neutrophils in the blood. ATG-Tr reduced circulating lymphocytes to lower levels and partially attenuated the rise in neutrophils. The in vivo effects of ATG, Tr, ATG-Tr, and ATG mixed with Tr (ATG + Tr) on thymus cells, spleen cells, T lymphocytes in the spleen, and rejection of a foreign skin graft were compared. Tr decreased all cell types, especially thymocytes, but did not delay graft rejection. ATG and ATG-Tr decreased thymocytes, eradicated T cells from the spleen, and delayed graft rejection 3-fold. ATG + Tr decreased thymocytes as Tr had done, eradicated T cells from the spleen, and delayed graft rejection 5-fold. It was concluded that ATG-Tr possessed antithymocyte antibody activity and Tr alkylating activity, but did not confer an immunological advantage over ATG alone, and that ATG and Tr mixed together unbound acted synergistically to delay graft rejection.

Effect of heat treatment on chromosomal aberrations induced by the alkylating agent trenimon or the restriction endonuclease Alu I in Chinese hamster ovary (CHO) cells.

Heat treatment of CHO cells in the G1-phase of the cell cycle leads to chromatid-type aberrations in first posttreatment metaphases. Posttreatment of heat-treated cells with the alkylating agent trenimon leads to a synergistic effect on the production of chromatid-type exchanges. These results indicate that heat induces lesions which like the lesions produced by trenimon give rise to chromatid-type aberrations during the first posttreatment S-phase, and that these lesions can interact with each other to produce chromatid-type exchanges. Treatment of CHO cells in the G1-phase of the cell cycle with the restriction endonuclease Alu I induces chromosomal aberrations. Pretreatment of cells with heat leads to a reduction of Alu I induced chromosome-type aberrations. When cells are allowed to recover after heat treatment for 22 h, the aberration frequencies produced by Alu I are the same as in cells not treated with heat. These findings can be explained by assuming that heat-induced accumulation of accessory proteins in the chromatin protects the DNA from being cut by Alu I, and that the cells recovered from the heat-induced protein accumulation after 22 h.

[Effect of long term treatment with trenimon in chronic progressive polyarthritis]. / Uber den Langzeittherapieeffekt von Trenimon bei Polyarthritis chronica pprogressiva

It is reported on the therapeutic effects with trenimon in patients with rheumatoid arthritis half a year and one year after the end of the treatment. When critically judged the quota of success was 32.5% for the total judgement after half a year. Significant relations dosis-effect could be ascertained only for the parameters of clinical activity up to 1 year and humoral inflammatory signs after half a year. When the therapeutic success is assessed in any case the additional therapeutic expenditure must be taken into consideration. Before the beginning of the therapy there was no ascertained relation between success of therapy and duration of the disease, sex, age, activity and function.

The effect of in situ isolated perfusion of experimental renal tumors with cytotoxic agents in high concentration.

In animal experiments the possibility of increasing the dosage of anticancer drugs by isolated in situ tumor perfusion without incurring systemic toxicity was studied. Isolated perfusion of normal kidneys with tris-ethylenimino-benzochinon (triaziquon, Trenimon) and amethopterin (Methotrexate) demonstrated that the kidney tolerates far higher antitumor drug concentrations than are achieved by systemic anticancer chemotherapy. Renal function, which was evaluated before and after cytotoxic perfusion by means of renal functional scintigraphy, decreased by less than 15%. Each kidney was examined histologically after perfusion. Isolated cytotoxic perfusion of renal tumors (Walker carcinosarcoma 256) using the combination of Trenimon (0.034 microgram/ml) and Methotrexate (0.034 mg/ml) led to complete tumor regression. Tumor perfusion without cytotoxic agents and systemic intravenous administration of the LD50 of the anticancer drugs did not achieve tumor control.

Inhibition of a mouse hepatoma by the alkylating agent Trenimon linked to immunoglobulins.

Trenimon was conjugated in active alkylating form to rabbit anti-mouse H6 hepatoma globulin (AHG) with retention of antibody activity. H6 hepatoma-inoculated mice were given various combinations of conjugates, free Trenimon, and unconjugated immunoglobulins in daily injections for 5 days. Linkage of Trenimon to immunoglobulins reduced systemic toxicity of the drug, with comparative retention of its antitumor activity. The antitumor action of Trenimon was potentiated by AHG irrespective of whether the drug was directly linked to AHG or free AHG was administered along with Trenimon linked to normal rabbit globulin (NRG). In vitro, Trenimon bound to AHG was less inhibitory to hepatoma cells than free Trenimon, but more inhibitory than Trenimon-NRG conjugates. There was no significant endocytosis of conjugates by the hepatoma cells. This suggests that unlike free Trenimon, the target molecules of Trenimon-immunoglobulin conjugates are not intracellular DNA but are located on the surface of the hepatoma cells.

[Histoautoradiographic examinations of benign and malignant cells and tissues during therapeutic interventions in gynecology]. / Histoautoradiographische Untersuchungen benigner und maligner Zellen und Gewebe während therapeutischer Massnahmen in der Gynäkologie.

The alteration of the proliferation activity of different tissues of the female genital tract was studied with the histo-autoradiographic method. Tissue samples from 1. the normal endometrium before and under treatment with the sequential oral contraceptive Ovanon, 2. carcinomas of the vulva before and under treatment with Bleomycin, 3. cervical carcinomas stage I-III before and under Co 60-radiation, and fluid material of cystic ovarian tumors and effusions before and under treatment with alkylating agents were incubated in 3H-thymidine. Morphologic and histo-autoradiographic alterations were observed during all investigations. It was demonstrated that the histo-autoradiographic method 1. gives informations about the proliferation activity of tissues of the female genital tract, 2. quantifies the success of treatment, 3. and allows prognosis about therapeutic results, as it was shown in the case of radiation sensitivity of cervix carcinomas.

[Experiences with cytostatic treatment of malignant tumors]. / Erfahrungen mit der zytostatischen Behandlung maligner Tumoren

The methods and the results of the cytostatic permanent and impact therapy, of the partial synchronisation as well as of the cytostatic combination treatment are described, taking into special consideration inoperable or metastasized solid tumours. From the study which was carried out during a period of 15 years results that a combination treatment referred in the individual doses to body weight and blood picture apparantly achieves better results than the other forms of therapy, whereby the risk of complications is relatively low.