Effect of the antineoplastic substance brotheophine on the insertion of precursors into nucleic acids and proteins from Plisse lymphosarcoma

The effect of antitumor medicine Brotheophine to insertion of the marked precursors into DNA (14[C]-timidine), RNA (3[H]-orotic acid) and proteins (14[C]-leucine) of tumor cells (Pliss lymphosarcoma) as the indices of biosynthetic processes was investigated. It has been shown that Brotheophine acts as an antimethabolite of purine exchange and inhibits the vertical genetic information transfer in tumor cell (DNA-RNA-protein). Namely, a significant inhibition of 14[C]-timide insertion to DNA has been observed. less distinct is the inhibition of 3[H]-orotic acid to RNA und 14[C]-leucine to proteins. The above revealed allows to assume that during Brotheophine treatment certain changes in DNA biosynthesis take place leading to synthesis of slightly transformed RNA with subsequent impairment of proteins synthesis.     

Modification of the State of Adrenergic Systems: Effects on Experimental Tumor Growth and Antitumor Activity of Chlofiden

We studied the effects of treatments with adrenaline hydrochloride, obsidan (a -adrenoblocker), melipramine (an inhibitor of monoamine uptake by neurons), and reserpine (a sympatholytic drug) on tumor growth (Pliss' lymphosarcoma in rats) and on the antitumor activity of a novel cytostatic drug, chlofiden. We found that adrenaline and reserpine enhanced the antitumor effect of chlofiden. Isolated applications of adrenaline and melipramine exerted slight antitumor effects, while after reserpine treatment there was a trend toward stimulation of tumor growth. Under the conditions of the model used, obsidan demonstrated no noticeable antitumor activity and did not modify the antitumor effect of chlofiden. Possible mechanisms of the observed effects are discussed.     

Cytostatic effects of bifolar and chlofiden. Effect on protein synthesis and cell cycle

Study of influence of new antitumor preparations bifolar and chlofiden on rat liver protein biosynthesis in vivo and on sarcoma-45 in vitro was carried out using labeled precursor 3H-leucine. It was shown that the preparations inhibited protein synthesis in normal and malignant tissues. Mitotic cycle and its phases were investigated with 3H-tymedin. It was established that bifolar influenced all the phases of mitotic cycle and the sensitive phases of the mitosis itself, which are connected with the redistribution of genetic material.     

Protein synthesizing cell apparatus in malignant growth and pharmacotherapy by chlofiden

Data on the influence of a new antitumor preparation chlofiden on the general contents of rat liver ribosomes and sarcoma 45 and their division on free and membrane of membrane bound and decrease of free ribosomes during tumor growth supposed synthesis of specific proteins bound are given in the paper. It was shown that in the liver of tumor bearing rats total and membrane bound ribosomes decreased and the level of free ribosomes increased. High contents of free ribosomes in sarcoma 45 may testify increase of intracellular protein synthesis including processes of cell growth and division as well as the tendency for increase. Chlofiden normalized total contents, increased free and decreased liver membrane bound ribosomes contents, during tumor growth supposed synthesis of specific proteins. Increase of free ribosomes and decrease of their specific radioactivity in sarcoma 45 testified membrane damage by chlofiden and inhibition of intracellular protein synthesis which are essential in cell division.     

Effect of bifolar and chlofiden on DNA synthesis of sarcoma 45 cells and on mitotic activity of rat small intestine epithelium

Results of the study on the influence of new antitumor preparations chlofiden and bifolar on sarcoma 45 DNA synthesis and on mitotic activity are given. It was shown that bifolar and chlofiden led to inhibition of label incorporation into DNA (3H-thymidine). Inhibition of mitotic activity after injection of both preparations in toxic doses (DL50) was revealed. During injection of the bifolar functional character of changes was established that is mitotic activity of the preparation during injection was restored.     

Effect of diiodobenzotefa on the functionally different subpopulations of T-lymphocytes]

Diiodobenzo-tepa (DIB) was given orally to CBA mice in a dose of 25 mg/kg for 3 successive days. The number of nucleus-containing cells decreased 3.9 fold in the thymus and 1.4 fold in the bone marrow. In experiments on transplantation of lymphoid cells to intact or lethally irradiated (CBA X C57BL/6J)F1 mice treated with DIB this substance did not influence the helper activity of T lymphocytes but inhibited the activity or B and T lymphocytes, inducing "graft-versus-host" and T cell-suppressor functions.     

Mechanism of action of a novel antitumor preparation of chlofiden. Effect on RNA synthesis

Study of the influence of the antitumor preparation chlofiden on RNA synthesis by sarcoma 45 and liver cells was carried out using 14C-orotic acid. Chlofiden was shown to activate RNA transport from the nucleus to the cytoplasm, and to reduce label incorporation into the nuclear and cytoplasmic RNA. Chlofiden increased the rate of RNA processes, which promoted some increase of label incorporation into low molecular RNA fraction of the nucleus and the cytoplasm. High and stable antitumor activity of chlofiden on sarcoma 45 was established.     

Cytotoxic effect of antineoplastic substances and their effect on DNA synthesis and cGMP level in tumor and normal tissues

The cytostatic effect of antitumour agents line on the level of malignantly changed actively proliferating system (tumour growth) and normal actively proliferating system (splin) was investigated on the basis of DNA synthesis and cGMP rate. Studies of these antitumour agents were carried out on three tumour growth models (Pliss lymphosarcoma, Yablonovskaya glyoblastoma and human glyoblastoma heterografts (subcapsular test). It has been demonstrated that chlofiden, brotheophine, vincristine, adriablastine, natulan, phthorafur have a marked and stable effect of DNA synthesis inhibition, resulting in their marked cytostatic effect and antitumour action stability under the therapy conditions. The experimental data have shown cGMP rates decrease in Pliss lymphosarcoma in the case of high antitumour activity.     

Effects of modulation of the cholinergic system activity on the experimental tumor growth and antitumor activity of chlofiden

We studied the influence of an anticholinesterase agent, proserine, and an m-cholinoblocker, atropine, on the growth of Pliss lymphosarcoma in rats and on the antitumor activity of a cytotoxic drug, chlofiden. It has been demonstrated that proserine stimulates tumor growth and decreases the antitumor efficacy of chlofiden. Injections of atropine evoked opposite effects: inhibition of the tumor growth and an increase in the, antitumor activity of chlofiden. Possible mechanisms of the above effects are discussed.