16 The Antitumor and Antiviral Effects of Polycarboxylic Acid Polymers
Downloaded by UNIV LAVAL on July 12, 2016 | http://pubs.acs.org Publication Date: May 12, 1982 | doi: 10.1021/bk-1982-0186.ch016
RAPHAEL M. OTTENBRITE Virginia Commonwealth University, Department of Chemistry, Richmond, VA 23284 and Medical College of Virginia Cancer Center, Virginia Commonwealth University, Richmond, VA 23298 Anionic and cationic polyelectrolytes of both natural and synthetic origin have been found to exhibit an inhibitory effect on viruses, bacteria, tumors, and enzymes (1). Polyanions, i n particular, have a broad range of biological activity and have received considerable interest in the areas of oncology and virology. The prolonged protective action of synthetic polyanions when given prior to virus inoculation has tremendous c l i n i c a l potential; consequently, establishing an impetus for assaying the fundamental role of polyanions i n controlling host resistance to a variety of pathophysiology. Synthetic polyanions, in particular, are known to produce a wide spectrum of effects on immune reactivity (1). They have been shown to induce production of interferon (2) modify RES function (3) and to have immunoadjuvant (4) a n t i v i r a l (5) and anti-tumor activity ( 6 ) . The antineoplastic activity of pyran copolymer has been largely attributed to i t s a b i l i t y to activate macrophages (7). One of the most interesting anionic polymers is pyran copolymer which is prepared from divinyl ether and maleic anhydride through copolymerization. It has been under investigation i n cancer chemotherapy for several years and is designated as NSC 46015 by the National Cancer Institute. It shows a variety of biological a c t i v i t i e s and has e l i c i t e d a considerable amount of interest by several researchers i n different areas. Pyran copolymer is an inducer of interferon (8-11); it has activity against a number of viruses (6-14), including Friend leukemia, Rauscher leukemia, Moloney sarcoma, polyoma, vesicular stomatitis, Mengo, encephalomyocarditis, MM, and foot-and-mouth disease; i t has antibacterial (21-23) and antifungal activity (21); it stimulates immune response ( 1 8 - 2 M ; i t inhibits adjuvant disease (31); it is an interesting anticoagulant (3g); and i t shows promise in removing plutonium from the l i v e r (33). However, the toxicity of the copolymer, although much lower than that of other anionic polymers which have been investigated, was apparently still too high for i t to be used extensively i n c l i n i c a l investigations 0097-6156/82/0186-0205$5.00/0 © 1982 American Chemical Society Carraher and Gebelein; Biological Activities of Polymers ACS Symposium Series; American Chemical Society: Washington, DC, 1982.
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BIOLOGICAL ACTIVITIES OF POLYMERS
(3^ 35) • Recent studies have shown that low molecular weight fractions and the calcium salt of the polymer are much less toxi c . This has stimulated further c l i n i c a l investigation of this drug. 9
Downloaded by UNIV LAVAL on July 12, 2016 | http://pubs.acs.org Publication Date: May 12, 1982 | doi: 10.1021/bk-1982-0186.ch016
Antitumor and Antiviral Activity of Polycarboxylic Acid Polymers We have found that the structure and the molecular weight of the polycarboxylic acid polymers play an important role i n the biological activity e l i c i t e d by these materials (JL). These findings have been coorborated by Breslow (36) who has reported that fractionated pyran shows lower toxicity with lower molecular weight fractions with very l i t t l e variation i n antitumor activity. Hodnett (37) has also prepared a number of polycarboxylic acid copolymers which gave varying activity with structure against ascites sarcoma 180 tumor. The average increase i n survival time was 25%. He found that the most effective polymers were those with low molecular weight, high carboxyl group density and low pKa at physiological pH. We have prepared several different molecular fractions of pyran, poly(acrylic acid-co-maleic acid) PAAMA, poly(maleic acid) PMA, and poly(acrylic acid-co-3,6-endoxo-l,2,3,6-tetrahydrophthal i c acid) BCEP and evaluated their activity against Lewis lung carcinoma (Table I) andencephalomyocarditis (EMC) virus (Table I I ) . Table I.
Inhibition of Tumor Size with Polymer Molecular Weight' 13
POLYMER
PAAMA
