Polyanions antitumor activity

Since the pioneer work by Merigan in 1967 [1], many kinds of synthetic or natural polyanionic polymers have been examined for their biological activities [2-8], such as cytotoxicity, antiviral activity, antitumor activity, and immunomodulating activity. Although the biological results were interesting, the extent of activity for clinical application was still low. 

The antitumor activity of synthetic 5-FU derivatives, polymeric prodrugs having 5-FU unit, and physically 5-FU incorporated polymers has been investigated [44-55], Moreover recent attention has been focused on syntetic polyanionic polymers [41], and drug-polyanion conjugates have been prepared to evaluate the activities [56],... 

Synthetic polyanions, in particular, are known to produce a wide spectrum of effects on immune reactivity (l). They have been shown to induce production of interferon (2) modify RES function (3) and to have immunoadjuvant (U) antiviral ( ) and antitumor activity The antineoplastic activity of pyran copoly-... 

The toxicity of polycarboxylic acid polymers is more sensitive to polymer structure and molecular weight than antitumor activity. The acute toxicity is markedly decreased with decreasing molecular weight (Table VI and XI). Further,polyanion polymers have been shown to highly sensitize mice to bacterial endotoxin (39)> this activity is strikingly molecular weight dependent as shown in Tables VII and XI as well as dose dependent ( 3. The enhanced sensitivity to endotoxin by synthetic anionic polymers has been extensively studied, but the mechanism of action is still not understood (39)-... 

Abstract. Pyran Copolymer (Divema, NSC46015 ), a synthetic polyanion, divinyl ether maleic anhydride copolymer, has achieved clinical trial because of antitumor activity and its role as an anti-viral agent. Most of the previous biologic and clinical work with this agent has been done with pyran copolymer of an average molecular weight of 18000. (NSC46015). 

These studies suggest that (a) the biological toxicity of polyanions increases with molecular weight (significant toxicity increases occur above 15,000 MW and becomes serious over 50,000 MW) (b) antitumor activity does not appear to be molecular weight dependent (c) antiviral activity is related to molecular weight (it is diminished below 50,000 MW) and (d) sensitization to bacterial endotoxin is related to molecular weight in the case of pyran and seems to be affected by polydispersity of the polyanionic polymer. 

Methyl vinyl ether-MA copolymer has the property of inducing interferon production in animals, which is potentially useful for inhibiting the growth of Friends leukemia virus.The 2 1 divinyl ether-co-MA polyanion cyclopolymer, often referred to as PYRAN, has had extensive study, because of its antitumor and interferon inducer properties. Many structural modifications and derivatives of this copolymer also exhibit antitumor activity, interferon inducing capacity, and a wide spectrum of biological activity. Recent... 

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... 

Shown in Figure 6 are the results for a higher molecular weight (Mw 20,000) series of poly(MA-CDA)s. In the unmodified polyanion(MA-CDA-20K), no caicein was released over the concentration of 10 mg/mL, indicating that the interaction of unmodified poly(MA-CDA) with the liposomal membrane is very weak. This may be why a very high dose of poly(MA-CDA) is necessary for observable antitumor activity in vivo. 

Another mechanism which is often claimed to be responsible for the antitumor and antiviral effects of some polymers is the induction of intraferon . Interferons are glycoproteins produced by the animal cell as a response to the interaction with foreign molecules called inducers The most potent inducers are natural double-stranded RNAs which are contained in many viruses. However, many other macromolecules, mainly polyanions, are also active. Cell cultures or animal experiments can be used for testing the induction activity. 

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