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The effects of bifunctional alkylating agents on DNA synthesis in sensitive and resistant Yoshida cells.

The effects of the alkylating agents methylene dimethanesulphonate (MDMS), sulphur mustard (SM) and methyl methanesulphonate (MMS) on DNA synthesis have been investigated in Yoshida sarcoma cell lines sensitive (YS) and resistant (YR) to these agents. Measurement of overall DNA synthesis by [3H]thymidine uptake into DNA indicated that both MDMS and SM, but not MMS, induced a greater depression of DNA synthesis in YS cells than in YR cells. Analysis of the sizes of newly synthesised strands of DNA by pulse labelling and alkaline sucrose gradient sedimentation revealed that MDMS inhibited the initation of new replicons and also reduced the size of new DNA strands. The relative extents of inhibition of replicon initation in MDMS-treated YS and YR cells were similar and reduced by caffeine while YR cells were comparatively less sensitive to the effect of MDMS on the sizes of DNA molecules synthesised. Similarly, YR cells apparently synthesised longer DNA strands following SM treatment compared to YS cells suggesting an association between the size of DNA molecules synthesized and the sensitivity of Yoshida cells to bifunctional alkylating agents.

Alkylating Agents↗

Repair of potentially lethal X ray damage and possible applications to clinical radiotherapy.

The relationship of potentially lethal damage repair (PLDR) to clinical radiotherapy has not been studied in great detail. We have therefore examined the cellular and molecular basis of PLDR in bacterial, animal and human tumor systems and attempted to relate laboratory data to clinical fractionation schemes. We also have examined how the repair of potentially lethal damage may alter the therapeutic ratio by altering tumor radiocurability and normal tissue tolerance.

Animals↗

Studies on fractionated hyperthermia in experimental animals systems III. Uneven daily doses.

The effect of daily hyperthermia on the murine normal and tumor tissues was investigated. Tumors were early generation isotransplants of a fibrosarcoma (FSa-II) and a mammary carcinoma (MCa) in C3Hf/Sed mice. Hyperthermia was given by immersing animal feet into a water bath at 45.5 degrees C. Tumor response was studied by TG time assay (determination of the time required for half of the treated animals' tumors to reach 1000 mm3 from the treatment day). Average peak foot reaction was also investigated to compare the therapeutic effectiveness of various fractionation regimens. In the first experiment the first dose (D1) of 10 min was followed by 10, 20, or 30 min daily doses. The treatment regimen "D1 of 10 min + daily 30 min" resulted in a significant therapeutic gain. The smaller doses were unable to overcome the repopulation of surviving tumor cells and the increasing magnitude of thermal resistance. To overcome tumor cell repopulation and thermal resistance, a regimen of increasing daily doses was attempted without success. These results indicated that doses following a D1 of 10 min must be as large as 30 min to obtain a therapeutic gain. Any fractionation regimens for MCa tumors, which developed the greatest thermal resistance among our animal tumors tested, failed to result in a therapeutic gain.

Animals↗

The influence of tumor immunity suppressors on the effector stage of human and animal lymphokine-activated killer cells.

Spleen cells of tumor-bearing mice suppressed the cytolytic activity of syngeneic LAK cells when added to the mixture of LAK cells and target cells at the beginning of the cytotoxicity test. Spleen cells of MC 14 tumor-bearing mice acquired the suppressor potential as early as 10 days after tumor transplantation; the suppressor activity in the EL 4 and X63-Ag8.653 tumor-bearing animals was first revealed at the 30th day and manifested itself up to the 120th day. The suppressor activity was expressed in a dose-dependent manner, both by unfractionated spleen cells and nylon wool-passed and plastic-adherent sub-populations. Similar results were obtained during the analysis of anti-tumor immunity suppressors in bladder cancer patients. MNC, nylon wool-passed and plastic-adherent cells of patients with stages I-II disease suppressed the cytotoxicity of autologous LAK cells in 2/6 cases; all patients [4] with III-IV stage possessed such suppressor activity. Presumably, the tumor growth induces the activity of suppressor T cells and monocytes/macrophages. The suppressor activity can interfere with the antitumor effect of autologous (syngeneic) LAK cells at the effector stage.

Animals↗

[Inhibition of tumoral graft growth by pretreatment with normal or heat-modified tumoral cells].

The intravenous injection of Ehrlich tumour cells (TC) into Swiss mice, or BP8-fibrosarcoma cells into C3H mice, caused no intra-organ dissemination of the tumour but resulted in increasing resistance of animals to these two tumours. The percentage of mice protected against a regularly lethal dose of TC given intraperitoneally (i.p.) increased with the dose and the number of immunizing injections to the i.p. challenge. However, after high or repeated doses a cancerous nodule sometimes developed at the site of intravenous injections (penis vein), which caused death of the animal, not by extension of the tumour but by urethral occlusion. Moderate heating (46, 49.5 or 52 degrees C) of the TC did not impair their immunogenicity but prevented their multiplication in normal mice. It was thus possible, by intradermal injections of heated TC, to protect mice against a dose of intact TC. The efficiency of prophylaxis depended on the temperature to which the cells were exposed (optimal temperature depending on the type of tumour), on the number of injections and on the medium in which the cells were suspended. When Freund's complete adjuvant was used, all mice were protected against tumour ascites following challenge.

Animals↗

Propionibacterium acnes-metabolites inhibit experimental lung metastasis of murine sarcoma L-1 in BALB/c-mice.

Adhesive interactions between tumor cells and host tissue occur at several stages of metastasis. Such interactions might be inhibited by microbial metabolites resembling the binding regions of matrix molecules. Certain metabolite sequences including Gly, Asp, Arg, and Ser (GAAS) proved to be critical for cell interactions, e.g. with fibronectin. In vitro, the rosette formation of murine pulmonary cells and sarcoma L-1 cells decreased significantly in the presence of Propionibacterium acnes-metabolites rich in GAAS. In vivo, coinjection of Propionibacterium acnes-metabolites and sarcoma L-1 cells significantly inhibited the formation of lung colonies in BALB/c mice. The inhibition of lung colonization by these metabolites appeared to be noncytotoxic and obviously did not result from impairment of cellular tumorigenicity.

Amino Acid Sequence↗

Inhibitory effect of Toxoplasma lysate antigen on the multiplication of transplanted tumor in mice.

Tachyzoites of the RH strain of Toxoplasma gondii were pretreated by a process of freezing and thawing followed by ultrasonication. After ultracentrifugation at 144,000 g for 120 minutes, the resulting supernatant contained a protein (TLA 144), which consisted mainly of a component of protozoan origin with a molecular weight of 10,000-20,000, and additional sugars, peptides, and amino acids. TLA 144 was soluble in water and of very low toxicity. Mice that had been inoculated with allogeneic (S-180) and syngeneic (Meth A) transplantable tumor cells, were injected intramuscularly with 100 micrograms of TLA 144 once a week for some time beginning one week after transplantation. It was found that after TLA treatment the multiplication of tumor cells was more intensely inhibited than following administration of OK-432, one of the biological response modifiers (BRMs).

Animals↗