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Poly-L-lysine, a synthetic cationic polypeptide known for its ability to bind to cell membranes, was found to induce differentiation of Friend leukemia cells « in vitro ». Studies were extended to the same « in vivo » model, in order to examine the therapeutic potential of this new differentiating agent. The i.p. administration of the polymer (Mw 2700) at the maximal tolerated dose resulted in major alterations of disease-related parameters. In particular, a multiple treatment schedule on the advanced disease resulted in a successful reduction of target organ weight and peripheral white blood cell count and appreciable differentiation of spleen and bone marrow cells. Apparently, the effects of poly-L-lysine were superior to those produced by N-methyl-acetamide, a potent inducer of differentiation « in vitro ».

The effects of medroxyprogesterone acetate (MPA) on differentiation were examined using mouse erythroleukemia (MEL) cells and compared with those of antiinflammatory agents. MPA at low doses (10−6- 10−7M) induced 10–15 % cells to differentiate, whereas high doses (10−4- 10−5M) caused a 30 % inhibition of dimethylsulfoxide (DMSO)-induced differentiation. Dexamethasone (10−4- 10−8M), a steroid antiinflammatory agent, significantly inhibited (77–70 %) DMSO-induced differentiation, whereas indomethacin, aspirin, flurbiprofen and BW755c (non steroid antiinflammatory agents) at the same concentrations had no effect. If added 24 h before DMSO, the inhibitory effects of MPA and dexamethasone increased to 65 % and 95 %, respectively, whereas indomethacin (10−5M) caused only a 30 % inhibition and the other drugs were inactive. None of these antiinflammatory agents affected differentiation when used without DMSO. MPA and dexamethasone inhibitory effects on DMSO-induced differentiation did not seem to be mediated through the inhibition of the synthesis of prostaglandins, since non-steroid prostaglandin inhibitors were slighly active only when added 24 h before DMSO.

Administration of attirinone, a new inotropic agent, markedly reduced acute lethal toxicity in normal female Swiss and male BALB/c mice given lethal doses of doxorubicin. Because attirinone abolished the negative inotropic effect of doxorubicin in isolated guinea pig atria, it was suggested that partial protection from acute toxicity of the antitumor antibiotic is directly related to protection of cardiac function.

Cell survival in response to doxorubicin (Dx) and cis-diammine-dichloroplatinum (cis-Pt) administration, either alone or combined with hyperthermic treatment, was analyzed in human osteosarcoma (U-2-OS), murine melanoma (B16V) and murine leukemia (P388) cell lines and in Dx-resistant sublines derived from B16V and P388. In all cell lines tested there was an enhancement of drug toxicity by hyperthermia. In U-2-OS, the increase was more pronounced for cis-Pt than for Dx. In B16V and in P388, the increase in Dx toxicity was of the same degree in Dx-senstitive and Dx-resistant sublines, whereas heat-induced sensitization to cis-Pt was higher in Dx-resistant sublines than in their Dx-sensitive counterpart. Analysis of the protein pattern in the various cell lines showed that the synthesis of heat-shock proteins induced by heat was not influenced by the combined use of drugs and heat. Moreover, in spite of some differences in the overall protein pattern, no significant differences in the basal levels of heat-shock protein synthesis or in the extent of its induction after heat shock were observed between murine cell lines relatively sensitive to Dx and their corresponding selected resistant cells.

It has been shown that ICRF-159 [1,2-bis(3,5-dioxopiperazine-1-yl)propane] and its more water soluble d-enantiomer, ICRF-186, antagonize the toxicity of daunorubicin and the cardiac toxicity of daunorubicin and doxorubicin and potentiate the antitumor effect of both substances in experimental animals. In particular, the antagonism against general toxicity was observed in combination with daunorubicin but not with doxorubicin. In this study, we evaluated the activity of ICRF-159 and ICRF-186 on the colony inhibition test of HeLa cells in vitro in combination with daunorubicin or doxorubicin. ICRF-159 and ICRF-186 similarly antagonize the cytotoxicity of daunorubicin but not of doxorubicin. There were no differences between ICRF-159 and ICRF-186, dissolved in DMSO and in physiological solution, respectively. The different activity of ICRF-159 and ICRF-186 against daunorubicin and doxorubicin is not explained by a different uptake of the anthracyclines by HeLa cells in vitro. In the present paper we report findings from our in vitro colony forming assay with HeLa cells, which has been used to evaluate the cytotoxicity of ICRF-159 and ICRF-186 in the presence of daunorubicin and doxorubicin.

This paper reports the effects of daunorubicin and adriamycin on DNA and RNA synthesis of in vitro cultured mouse embryo fibroblasts (MEF) stimulated by fetal calf serum (FCS). The addition of FCS to quiescent MEF cultures brings about a wave of RNA synthesis, followed by DNA synthesis which starts between 8 and 12 h after change of medium and proceed for up to 24 h. These cells are therefore partially synchronized. The level of DNA synthesis depends on the amount of FCS added. Daunorubicin and adriamycin are almost equally effective in inhibiting DNA synthesis, as well as cell proliferation, which takes place later. Adriamycin is more active than daunorubicin on RNA synthesis. In cultures treated for an 8 h period starting at different times after FCS addition, the highest DNA synthesis inhibition is achieved by treatment during the first 8 h, when DNA synthesis has not yet started. The cellular uptake of daunorubicin is constantly higher than that of adriamycin, in any experimental condition tested. The results show that FCS-stimulated MEF can provide a simple method for studying the effects of anthracycline antibiotics on partially synchronized cells.

The aim of the present study was to examine the phenotypic heterogeneity of murine and human melanoma cell lines with particular reference to anticancer drug sensitivity, growth pattern and susceptibility to lysis by lymphokine (rIL2) activated killer (LAK cells). Clones selected for a different drug sensitivity were tested to evaluate the stability of such properties after different in vitro passages. A possible relationship between drug sensitivity and LAK susceptibility was also analyzed. The results indicated a high heterogeneity in murine and in human melanoma clones for all the parameters. However, drug sensitivity, which was stable although for only a few passages in an untreated human melanoma, was highly unstable in murine naturally or drug-induced resistant cells. Finally, whereas human drug-resistant clones were sensitive to lysis by LAK cells and an inverse correlation was found with the level of drug resistance, murine clones appeared to be LAK sensitive, and no correlation was found between the level of drug resistance and LAK sensitivity. Our data indicate a different stability in drug response of human and murine cells and a different behaviour of human and murine drug-resistant cells in response to LAK lysis.