Effects of intravascular laser irradiation of blood on growth and metastasis of lymphosarcoma in rats

The effect of intravenous blood radiation by low-intensity laser on tumour growth in Wistar rats with Pliss lymphosarcoma has been studied. As a result of single or double blood radiation by laser with wave-length of 510 and 633 nm both the tumour growth inhibition and metastases disappearance have been shown.     

The effect of 5-fluorouracil, metronidazole, caffeine and irradiation on the synthesis of DNA in the Pliss lymphosarcoma

Injection of 5-fluorouracil or caffeine or a combination of each of them with metronidazole removes partially or wholly the postirradiation arrest of DNA synthesis in Pliss lymphosarcoma and increases the label index and (or) the rate of its incorporation in nuclei of DNA-synthesizing cells compared to irradiated controls. The administration of the three agents arrests almost completely the DNA synthesis during the very first hours following irradiation, then prematurely removes partially the synthesis block in most DNA-synthesizing cells.     

Effect of the diuretic diacarb on the antitumor activity of the antibiotics rubomycin and olivomycin]

Combined use of rubomycin and olivomycin with diacarb in treatment of rats with Pliss lymphosarcoma increased the antiblastomic activity of the antibiotics. The antitumor effect of rubomycin and olivomycin was increased by diacarb in the same degree as that of dipin, a synthetic cytostatic.     

Conventional and prospective molecular targets in antitumour drug design. Concepts in antitumour research.

To introduce a rationale in a drug development program the molecular base of the pathological lesion must be carefully considered both for selecting test compounds and to apply the most appropriate assay systems. From the beginning of antitumour drug research the principal aim has always been to select chemical compounds which could selectively inhibit tumour growth. This strategy was in full harmony with the concept that tumours are build up by fast proliferating cells. Research based on this concept has resulted in the development of more than 40 cytostatic agents, which are rather diverse in their chemical properties, but all act on one of the molecular mechanisms participating in cell proliferation. However the unsatisfactory therapeutic responses which could be obtained by the cytostatic agents focused the attention on those molecular events in the tumour cells which may be more closely related to the progression of the malignant disease.     

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.     

Antitumour activity of endotoxin, concanavalin A and poly I: C and their ability to elicit tumour necrosis factor, cytostatic factors, and interferon in vivo

Summary Concanavalin A, endotoxin, poly I : C, and tumour necrosis serum (TNS) were compared for antitumour activity against Meth A sarcoma transplanted in syngeneic BALB/c mice and their capacity to induce tumour necrosis factor (TNF), heat-stable cytostatic factors, and heat-labile interferon in the blood of normal and Corynebacterium parvum-pretreated mice. All the agents induced hyperemia and inhibition of mitosis at 4 h, and by 24 h many tumours had a dark necrotic centre. Subsequent tumour growth was inhibited and in some of the treated mice tumours regressed completely. Poly A : U and normal mouse serum did not induce regression and their effects were less marked in all other respects, suggesting that these events may be linked. The necrotizing effects of concanavalin A and poly I : C are unlikely to be mediated by TNF, because neither agent could mimic endotoxin in eliciting RNase-resistant necrotizing and regressing activity in the serum of mice pretreated with C. parvum. Poly I : C did not induce strong cytostatic activity in the sera of C. parvum-treated mice, and for this and other reasons these factors are unlikely to be responsible for the observed effects. Concanavalin A, endotoxin, and poly I : C induced high levels of serum interferon but purified interferon had only weak antitumour activity in the Meth A system, suggesting that interferon may not be the mediator.From these and other data it is concluded that there is no clear relationship between the capacity of the agents to induce tumour necrosis and their capacity to elicit TNF, cytostatic factors, and interferon.     

Modification of the radiosensitizing effect of metronidazole by 5-fluorouracil and caffeine

A study was made of the combined effect of 5-fluorouracil, metronidazole, caffeine and radiation on radiosensitivity of Pliss lymphosarcoma and protein synthesis rate during the first few hours following irradiation. A complete regression of the tumor was noted in 100% of animals after a 3-fold exposure. Effective postirradiation inhibition of protein synthesis was achieved by injection of metronidazole and caffeine together with 5-fluorouracil.     

The effect of therapy with cytostatics and immunomodulators on mitotic pathology in Lewis tumor cells in mice]

The effect of cytostatics (methylnitrosourea and methotrexate), immunomodulators (thymalin and reaferon) and their combinations on the mitotic pathology of mice Lewis tumour cells was studied. It was revealed that chemotherapy with these agents changed the interrelation between mitotic phases and somewhat enhanced the incidence of pathologic mitoses mainly connected with the damage of mitotic apparatus. Immunomodulators differently affected the cytostatic activity of antitumour agents that may be associated with their mechanisms of action.     

Comparative investigations on the effect of different dose schedules of the phase-specific drug vincristine (VCR) on the proliferation kinetics of a solid experimental tumour

The aim of the present investigation was to study the effect of a high bolus injection (1 X 2.1 mg) of vincristine (VCR) during the phase of tumour growth retardation at the 14th day after transplantation and to compare the findings with the results of single (1 X 0.35 mg) and repeated (6 X 0.35 mg) applications of this cytostatic drug. Furthermore, an attempt was made to induce a synchronization of tumour cell proliferation. It was found that the effect on the volume growth was very pronounced after the high bolus injection and the repeated application of vincristine compared with the single low dose of the cytostatic drug. A synchronization of the tumour cell proliferation by flow out of the mitotic block could not be demonstrated. On the other hand a modest simultaneous recruitment of previously non-cycling tumour cells into the cell cycle occurred in the periphery of the tumour after the high bolus injection. The repeated application and the high bolus injection of VCR increased the cytostatic effect, especially in the tumour centre, related to the more slowly proliferating tumour cell compartment.     

Role of tumour necrosis factor in the tumour-necrotizing activity of agents with diverging toxicity

Summary We investigated the ability of various tumournecrotizing agents with diverging toxicity to induce tumour necrosis factor (TNF) and cytostatic activity inPropionibacterium-acnes-primed Swiss and tumour-bearing BALB/c mice, and the capacity of anti-TNF antibodies to inhibit induction of tumour necrosis by the agents. Lipid A and especially its combination with muramyl dipeptide induced high TNF levels in Swiss mice, as measured in the serum. Lower levels were induced by detoxified lipid A and the nontoxic dsRNA, polyadenylic polyuridylic acid, either alone or combined with muramyl dipeptide. The toxic agents also appeared the strongest inducers of mediators with cytostatic activity against cultured endothelial cells and MethA tumour cells. Anti-TNF antibodies partially reduced the cytostatic activity of the sera against MethA cells. Tumour-bearing BALB/c mice produced only low levels of TNF and cytostatic factors in response to all agents. Recombinant mouse TNF hardly reduced the DNA synthesis of MethA cells, unless normal mouse serum was added. Serum fromP.-acnes-treated Swiss mice and tumour-bearing BALB/c mice, that were inhibitory on their own, failed to potentiate the action of TNF. Serum from Swiss mice treated with toxic, but not detoxified, lipid A caused extensive tumour necrosis upon injection into MethA-bearing BALB/c mice. This activity was completely abolished by pre-incubation of the serum with anti-TNF. The tumour-necrotizing activity of the agents could be partially reduced by prior injection of these antibodies. Results show that the capacity of the agents to induce TNF and cytostatic activity is not related to their antitumour potential. Although TNF is likely to be a crucial mediator of the tumour-necrotizing action of the toxic as well as the nontoxic agents, it is probably not the sole mediator. Data also indicate that induction of tumour necrosis does not require induction of high and, thus toxic, TNF levels in the serum.     

An experimental analysis of the interrelation of the kinetics of spontaneous blood serum chemiluminescence and of the kinetics of the tumor process

On the material of 5 strains of transplanted rat tumours (sarcoma 45, carcinoma Guérin, carcinosarcoma Walker, lymphosarcoma Pliss, erythromyelosis Shvets) and also mice tumours induced by Moloney and Rauscher viruses and on the models of chemical carcinogenesis of rats: lung (intratracheal injection of 3,4-benz(a)pyrene), breast (DMBA) and liver DENA) was shown that tumorous processes of various origin are accompanied by either elevation or inhibition of blood serum spontaneous chemiluminescence (SChL). In all investigated cases the extreme points of SChL curve coincide with the moment of change of tumour growth kinetics.     

Antitumor activity of normal human globulin: effects on murine and human erythroleukemic cells

The effect of the antitumor fraction isolated from the alpha 2-globulin region of normal human serum (NHG-I) upon murine (FELC) and human (K562) erythroleukemic cells in vitro was determined. NHG-I inhibited the growth of both actively growing FELC and K562 cells in a dose-dependent manner. However, it has no effect upon mitomycin C treated FELC which were unable to divide nor upon dimethylsulfoxide-induced FELC in stationary phase. These results indicate that NHG-I has a cytostatic effect upon cell growth and suggests that its action may be dependent upon DNA synthesis. This is in marked contrast to TNF, the alpha 2-globulin factor obtained from murine serum which is also not species-specific but whose action upon these cell lines is cytotoxic.     

Fatty-acid composition of lipids and physicochemical characteristics of membrane fractions and the membrane of endoplasmic reticulum of thymus and Pliss' lymphosarcoma

The paper is concerned with composition of neutral lipids and phospholipids, the regularity of lipid bilayer and structural reorganization of plasma membranes, and membranes of smooth and rough cell reticulum of thymus and Pliss lymphosarcoma are studied at linear and stationary growth phase. No qualitative differences are found in the fatty-acid composition of lipid membranes in normal and tumour cells. In plasma membranes of phospholipids and in membranes of smooth reticulum of tumour cells the unsaturated lipid component increases in the process of growth, the cholesterin/phospholipids ratio decreases, fluidity of the lipid bilayer diminishes and structural heterogeneity of these membranes rises while in membranes of rough reticulum the saturation of lipids increases, but the cholesterin/phospholipids ratio does not change. The temperatures of structural reorganization also does not change, which evidences for a less structural lability of membranes of rough reticulum as compared with other membranes.     

Comparative Investigations On the Effect of Different Dose Schedules of the Phase-Specific Drug Vincristine (Vcr) On the Proliferation Kinetics of A Solid Experimental Tumour

The aim of the present investigation was to study the effect of a high bolus injection (1 × 2.1 mg) of vincristine (VCR) during the phase of tumour growth retardation at the 14th day after transplantation and to compare the findings with the results of single (1 × 0.35 mg) and repeated (6 × 0.35 mg) applications of this cytostatic drug. Furthermore, an attempt was made to induce a synchronization of tumour cell proliferation. It was found that the effect on the volume growth was very pronounced after the high bolus injection and the repeated application of vincristine compared with the single low dose of the cytostatic drug. A synchronization of the tumour cell proliferation by flow out of the mitotic block could not be demonstrated. On the other hand a modest simultaneous recruitment of previously non-cycling tumour cells into the cell cycle occurred in the periphery of the tumour after the high bolus injection. the repeated application and the high bolus injection of VCR increased the cytostatic effect, especially in the tumour centre, related to the more slowly proliferating tumour cell compartment.     

Action of aureolic acid and dactinomycin group antibiotics on human brain tumors in culture]

The cytotoxic effect of antitumour antibiotics, such as dactinomycin, mithramycin, variamycin and olivomycin on the cells of the human brain tumours (multiform glyoblastoma, arachnoidendotelioma and astrocytoma) grown by the method of the primary plasmic culture was studied. Dactinomycin was superior to the antibiotics of the aureolic acid group in the rate and level of the cytotoxic effect on the tumour cells: 76 per cent of the above tumours were sensitive to dactinomycin, 56 per cent to mithramycin and 52 per cent to variamycin and olivomycin. Among the total number of the tumours sensitive to the drugs the number of the highly sensitive tumours amounted to 57.9 per cent for dactinomycin and 30.8--38.5 per cent for the antibiotics of the aureolic acid group. Definite differences in the efficiency of the antibiotics of the aureolic acid group with respect to different types of the brain tumours were observed.     

Cytoprotective effect of arginine deiminase on taxol-induced apoptosis in DU145 human prostate cancer cells

We purified and partially sequenced a cytostatic protein from the ASC-17D Sertoli cell-conditioned media (rSCCM) showing a molecular weight of 90 kDa with homodimeric composition. N-terminal amino acid analysis revealed that the protein was homologous to the arginine deiminase (ADI) of Mycoplasma arginini. We found ADI enzyme activity in rSCCM and the abolishment of the growth inhibitory effect by the supplement of L-arginine. Thus, we confirmed that the cytostatic activity in rSCCM was due to the depletion of extracellular L-arginine by ADI. Apparent increase of cell death or DNA fragmentation was not observed in DU145 cells cultured in the presence of ADI. Incubation of DU145 cancer cells with taxol resulted in a marked DNA fragmentation, whereas pretreatment with ADI or cycloheximide protected the cells from taxol-induced apoptosis. Preincubation of the cells with ADI inhibited S35-methionine incorporation into protein synthesis in a dose dependent manner. These data suggest that ADI-induced arginine depletion may inhibit protein synthesis, and result in the protection of apoptotic cell death that requires new protein synthesis.     

Factors reducing the superoxide dismutase activity of the liver of rats with Pliss lymphosarcoma

The procedures for isolation and purification of Cu/Zn superoxide dismutase (SOD) from small amounts of rat liver at different stages of Pliss lymphosarcoma growth were developed. Two stages of tumour growth were distinguished. At the first stage (4-5th day after reinoculation) the intensity of optical (680 nm) and EPR spectra of SOD was decreased, on the average, to 30%, while at the second stage--by 40% at 680 nm and by 32%, at 260 nm. The intensity of the EPR spectra was also diminished by 40% as compared to the control. It was assumed that at initial stages of tumour growth the decrease of the SOD activity is mainly due to the reduction of enzyme Cu, while at the second stage--to the decrease of the protein content. In all probability, the observed changes are induced by the activation of lipid peroxidation involving active O2 species. The second stage is associated with the superoxide-induced impairment of the function of nucleic acids involved in protein biosynthesis.     

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.     

The role of peritoneal macrophages in realizing the growth inhibiting effect of glucocorticoids on reinoculated murine hepatoma 22 cells: the effect of hydrocortisone on the cytotoxic activity and metabolism of phospholipids by macrophages

A single injection of hydrocortisone to rats with ascite hepatoma 22 had practically no effect on tumour growth. Inhibition of tumour growth was observed only after reinoculation of ascite hepatoma to mice that had received no less than 8 daily injections of the hormone. A single injection of hydrocortisone induced inhibition of the cytotoxic activity and decreased phospholipid metabolism in peritoneal macrophages. Contrariwise, long-term administration of the hormone caused marked activation of macrophage cytotoxicity. In this case incorporation of 32P into macrophage phospholipids was restored up to the control level. It is concluded that one of mechanisms underlying the inhibitory effect of glucocorticoids on macrophages is inhibition of phospholipid turnover. Presumably, long-term administration of the hormone promotes the formation of a new population of macrophages insensitive to the inhibitory effect of glucocorticoids and possessing a high cytostatic activity. The appearance of such activated macrophages may account for the enhancement of hydrocortisone effect on tumour cells upon prolonged administration of the hormone.