Antineoplastic activity of poly(L-lysine) with some ascites tumor cells.

Abstract

ABSIRACT We have found that poly(L-lysine) can be a very effective agent in preventing the growth of Ehrlich ascites tumors in mice. When given optimal doses of poly(L-lysine) (Mr 60 X 103) intraperitoneally for 5 consecutive days, beginning on day 1 after inoculation with Ehrlich ascites cells, White Swiss mice show nearly a 100% remission from subsequent tumor growth. Rechallenge of "cured" animals with tumor cells, however, shows no long-term immunological protection. In tissue culture, poly(L-lysine) shows a related potent cytotoxicity with HeLa cells; interestingly, the D isomer has properties strikingly different from those of the L isomer. In addition, there is a strong molecular weight dependence in that the small polylysine (Mr 3 X 103) possess less than 1/20th the cytotoxicity of large polymers (Mr 70 X 103) on a weight basis in both cell culture and animal studies. At the same time, none of these lysine polymers gives any significant increase in life span to BDF1 mice infected with L1210 murine leukemia cells. We have also further explored the mechanism by which the polylysines express their cytotoxicity. These data indicate that lysine polymers show cell specificity in their action and in some cases they may be beneficial as potent antineoplastic agents, particularly when molecular weight is taken into consideration. For more than 25 years, poly(L-lysine) has been known to have unusual biological properties. Early studies showed that it decreased the infectivity of tobacco mosaic virus (1), disturbed thrombin formation in rats (2), blocked the development of bacteriophage (3, 4), protected chicken embryos from animal viruses (5, 6), and possessed antibacterial activity (7). There was also an early report that indicated that polylysine had some activity against murine tumors (8). More recently, polylysine has been found to exhibit a large number of unique membrane properties. These include the ability to enhance the cellular uptake of macromolecules (9), to inhibit iodide uptake by thyroid slices (10), to produce pathogenesis of the glomerular epithelium (11), to act as an anticholinesterase (12), to specifically agglutinate the lymphocytes from cancer patients (13), and to either increase or decrease the transport of specific radioisotopes into cells (14). These effects are probably associated with the polycationic character of polylysine and are probably due to specific interactions on the cell membrane.Recently, we have been examining the ability of polylysine to serve as an efficient drug carrier (15). In doing the controls for these studies, we found that poly(L-lysitie)s of a certain Mr, (60 X 103) could induce 100% remissions in mice inoculated with Ehrlich ascites when the polymer was administered at increased doses. This paper presents results on the antineoplastic activity and toxicity as functions of polymer molecular weight and concentration. Also, we will provide further information into the mechanism accounting for the antineoplastic and cytotoxic activities of polylysine. MATERIALS AND ...

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“…In pharmaceutical applications poly-L-lysines (PLLs) and poly-Larginines (PLAs) serve as model compounds for the distribution of biologically active substances in organisms and different tissues [7]. It was shown that PLLs and PLAs in high concentrations have anticarcinogenic properties [8]. Cationic polypeptides also serve as models for cell toxic and antimicrobial peptides [9,10].…”

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