Macrophage pyran-activated

In addition, polyelectrolytes such as poly(acrylic acid-alt-maleic anhydride) (pyran) are reticuloendothelial stimulants, induce resistance to tumor growth [462,463] and show interferon-inducing ability and antiviral activity. The pyran activity may be dependent upon molecular weight. Low molecular weight materials of narrow polydispersity activate macrophages however antitumor activity does not appear to be molecular weight dependent [460]. 

Similar to the in vitro study using Lewis lung cells, it was observed that animals pretreated with pyran had no detectable Ehrlich ascites cells in phase GgM and only a few in the S phase after 2 or 6 days (Table XIV) (60) compared to pyran untreated mice which had 58 in the S phase and 22 in the GgM phase. Consequently, the use of pyran activated macrophage resulted in a) a high overall level of tumoricidal activity both in vivo and in vitro, b) the appearance of a tumor cell population with 50 of their normal DNA content and c) a shift of tumor cells from phase GgM to G. These results indicate that a possible mechanism of activated macrophage tumoricidal activity involves the induction of tumor cells with a reduced DNA content. 

Figure 3. The effect of concentration of pyran activated peritoneal macrophage cells (PMC) on Lewis Lung (LL) carcinoma and normal mouse embryo (ME) cell cultures. (At 10 PMC all the LL cells are killed while the ME cells are unaffected.

It has been observed that when pyran activated macrophages were cultured with Lewis lung tumor cells, the tumor cells DNA content was reduced by 50% but no tumor cell division took place. The decrease in DNA content resulted in tumor cell death as information essential for cell metabolism and/or replication was no longer available to the cell. 

Cell cycle analysis of Lewis lung tumor cells cultured with pyran activated macrophages (Table VI) shows a shift in the cellular population with time from G2M >S->-G. Thus, the population is shifting from states of mitotic activity to less active, senescent states with Increased time of incubation with activated macrophages. If the tumor cells are not dividing it is unlikely that they can do very much harm. Control studies indicate that normal or thioglycollate elicited macrophages to not cause this shift in tumor cell activity. 

TABLE VI, DNA Distribution of Lewis Lung Cell Cultivated With Pyran Activated Macrophages,... 

In vivo studies illustrate a similar phenomenon (Table VII). Pyran treatment of mice resulted in a marked decrease in mitotic activity (G2M) with a concommitant shift to the resting state (cp. These results indicate that a possible mechanism of activated macrophage tumoricidal activity involves the Induction of tumor cells with a reduced DNA content. 

The uptake and location of pyran into the macrophage is of central importance in understanding the mechanism(s) by which these polyanionic polymers activate the macrophage to tumoricidal capacity. Very few studies have been addressed to this question with the exception of those performed by Pratten et al. [35]. 

Activated macrophage were obtained from mice injected l.p. with 25 mg/kg of pyran 7 days before peritoneal lavage. 

For example, infection with a variety of bacteria will increase the effectiveness of the tumoricidal action of macrophages in vivo, A soluble lymphokine, produced by lymphocytes appears to be needed for this type of action. This poorly defined factor is called macrophage activating factor (MAF). In contrast certain interferon inducers, such as endotoxins and poly (I)-poly (C) can transform macrophages without the need for lymphocytes.24 Direct activation of macrophages by pyran copolymer and other polyanionic inducers without lymphocyte-derived MAF was also demonstrated.2 28 Since these inducers stimulate macrophages to produce interferon, and interferon activates macrophages, it is reasonable to think that interferon is the effective activator in these instances. 

The polyanions can function as chemical immunomodulators and produce a wide spectrum of effects on the immune system. It was reported that the polyanions have the capacity to activate macrophages, which may be related to their effects on the plasma membrane lipids, and to provide immuno-modulation through B-cell stimulation [8,9]. It was also observed that the antiviral, antibacterial, and antitumor activities of pyran copolymer may be mediated by the induction of interferon (IFN) production [10], macrophage activation [11], or stimulation of antibody-dependent cellular cytotoxicity... 

ADCC) [12]. The low molecular weight pyran copolymer (MVE-2, Mw 15,000) does stimulate natural killer (NK) cells [13,14], Thus, at least two cell types, the macrophages and the NK cells, are presumed to play an important role in the antitumor and antiviral activity of MVE-2. The enhancement of the macrophage and the NK cell activity by these immuno-modulators may have the potential to provide tumoricidal effects and protection against viral infections exacerbated during immunosuppression or immunodeficiency in cases such as acquired immunodeficiency syndrome (AIDS) and severe combined immunodeficiency disease (SCID). 

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