The use of liposomes as carriers of adriamycin (ADM) seems to offer important advantages with regard to the attenuation of the dose-dependent anthracycline-induced cardiomyopathy. This effect has been shown in rodents (Rahman et al., 1980(Rahman et al., , 1982Forssen & Tokes, 1981;Olson et al., 1982) and dogs (Herman et al., 1983) and is apparently related at least partially to the reduced uptake of the drug in the cardiac tissue of animals treated with liposome-entrapped ADM (L-ADM) (Forssen & Tokes, 1979, 1983 Rahman et al., 1980;Gabizon et al., 1982Gabizon et al., , 1983Olson et al., 1982). Obviously, if this delivery system is to be useful therapeutically, it is crucial to evaluate its anti-tumour activity. Since liposomes home preferentially in tissues with sinusoidal capillaries and rich in cells of the reticuloendothelial system, such as the liver and spleen (Segal et al., 1974;Poste et al., 1982), it is reasonable to assume that tumour colonies residing in these organs constitute a suitable target for liposome-mediated delivery of cytotoxic drugs. The purpose of this paper is to describe the antitumour In previous studies we showed that liposomes containing negatively charged phospholipids capture ADM very efficiently and cause important changes in the tissue distribution of the drug, viz. decreased levels in the heart and increased and sustained levels in the liver and spleen. These changes were observed in normal (Gabizon et al., 1982) and in tumour-bearing mice (Gabizon et al., 1983). Furthermore, when metastatic tumour cells were isolated from the liver we found significantly higher intracellular levels of ADM in tumour cells of mice treated with L-ADM as compared to free ADM treatment. Also, the proliferative ability of intrahepatic metastatic cells in in vitro qultures and in vivo transfer assays was markedly more impaired after L-ADM treatment than after ADM alone (Gabizon et al., 1983).These results, and especially the ability of liposomes to increase the intracellular levels of ADM in liver-residing tumour cells, provided a rational basis for therapeutic experiments. In the present study, we have compared the survival of tumour-inoculated mice treated either with L-ADM or with free ADM using the metastatic liver model of the J-6456 lymphoma. Our results suggest that the therapeutic index of ADM can be significantly improved by liposome association in a group of

Summary The effects of certain compounds on the in vitro growth rate and the sensitivity to doxorubicin of P388 murine leukaemia cell line and of a doxorubicin-resistant subline (P388/ADR) were studied.The calcium channel blocking activity of these compounds was evaluated by measuring their effects on the sodium-dependent and membrane potential-dependent calcium uptake in synaptic plasma membrane vesicles.At non-inhibitory concentrations, verapamil, dipyridamole, meclizine and nicardipine were highly active in restoring the sensitivity to doxorubicin of P388/ADR cells. Moderately active were propranolol, N-(,Bdiethylaminoethyl)-N-(,B-hydroxy-,B-phenylethyl)-2, 5-dichloranaline (MDL-6792), thioridazine and chlorocyclizine, while nifedipine, guanethidine, phentolamine, chloroquine and papaverine had zero or only minimal synergistic activity to doxorubicin in this cell line. Doxorubicin synergistic activity could not be demonstrated in the parent drug-sensitive cell line.No sodium-dependent or membrane potential-dependent calcium uptake could be demonstrated in vesicles prepared from plasma membranes of either cell line. There is no correlation between the ability of these compounds to inhibit calcium uptake in synaptic vesicles and their potency in restoring the sensitivity of P388/ADR cells to doxorubicin.

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Single doses of serine (250 mg/kg i.p.) failed to elevate central glycine in mice (1 h after injection), or to compensate for losses caused by implantation of morphine base (70 mg/animal), and reduced the jumping response to nalorphine (100 mg/kg i.p.). In contrast, sustained treatment with 250-mg/kg doses of serine at 24-hour intervals produced increases in brain and medullar glycine (1 h after 4th injection: 46–50 % in normal, 39–75 % in morphine-dependent mice, and enhanced the jumping response (40 % over controls).