Antitumor activity, polymers

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. 

Veronese FM, Schiavon O, Pasut G, Mendichi R, Andersson L, Tsirk A, Ford J, Wu G, Kneller S, Davies J, Duncan R (2005) PEG-doxorubicin conjugates influence of polymer structure on drug release, in vitro cytotoxicity, biodistribution, and antitumor activity. Bioconjug Chem 16 775-784... 

Chen R, meng F, Liu Z, Chen R, Zhang M. Antitumor activities of different fractions of polysaccharide purified from Ornithogalum caudatum Ait. Carbohydrate Polymers 2010 80 845-851. 

In recent years, many fungi were examined for potent antitumor polysaccharides and a great number of different carbohydrate polymers could be isolated and shown to have a quite distinct antitumor activity. The most active ones have p-1,3- and 1,6-linkages and glucose as the main structural monomer. 

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],... 

Keywords Imidazoles Polycychc derivatives Poly (arylimidazole) Polymer salt Antitumor activity... 

Caiolfa VR, Zamai M, Fiorino A, et al. Polymer bound camptothecin initial biodistribution and antitumor activity studies. J Control Release 2000 65 105-119. 

The 1 2 copolymer of dlvlnyl ether and maleic anhydride ("pyran copolymer," I) exhibits a broad range of biological activity, and has been discussed elsewhere in this volume and in earlier reviews (JL, 2) Of particular interest is the polymer s antitumor activity after initial clinical testing and then withdrawal from clinical use due to severe toxicity, the drug is again under evaluation as an agent for the treatment of human cancer. ... 

Polymer (VI) has been shown to have antitumor activity against adenocarcinoma 755, Dunning ascites leukemia. Friend leukemia virus, and Lewis lung carcinoma. In the latter case, polymer (VI) showed activity about equal to that of cyclophosphamide (an alkylating agent) and was more effective than 6-mercaptopurine (an antimetabolite) ( ). The DIVEMA polymer (V) Is also active against some cancer causing viruses such as Friend leukemia, Moloney sarcoma and Rauscher leukemia ( ). 

Monomers (VII) and (VIII) have been studied the most extensively. The original work on polymerizing (VII) lead to an intractable. Insoluble, cyclopolymerlzed polymer (40) but subsequent work lead to linear, water soluble polymers (jH, ). Monomer (Vlll) readily polymerizes under free radical conditions to form linear, water soluble polymers ( J,, ). The polymers of (Vll) and (Vlll) form complexes with each other in a manner similar to the natural nucleic acids (.25,2 and they do show antitumor activity against murine leukemia virus (45,46). 

The first 5-fluorouracil containing polymer had the 5-FU units in the polymer backbone and this structure is shown below as (XVI). This was claimed to be biologically active (47). More recently, monomer (XVII) was prepared by the reaction of 5-FU with methyl fumaroyl chloride. The polymers and copolymers of (XVII) do show antitumor activity but this may be due to the hydrolysis of this unit to release 5-FU (48). 

Polymer structure changes showed different effects in tumor size. All the polymers reduced the tumor growth by approximately T5% except for BCEP which only inhibited the growth by 30%. More importantly each polymer had a different effect on the increased life span (iLS) of the animal with pyran being the most effective (Uo% ILS) and BCEP the least (10% ILS). The molecular wei t did not have significant effect on the antitumor activity but did have a great effect on toxicity of the material which will be discussed later. 

MW Pyran Polymer Percent Lewis lung cytotoxicity mouse embryo fibroblast f Antitumor Activity P815 mastocytoma % ILS mg/kg pyran Required for 100% Protection Against EMC... 

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)-... 

His research contributions to polymer chemistry span many areas, from studies of alternating copolymers of maleic anhydride and vinyl ether ( pyran copolymer ) having interferon inducing capability and antitumor activity, to polymerization of triazoline diones and synthesis of the antiaromatic 3,3-dimethoxycyclopropene. 

Peng Y, Zhang L, Zeng F, et al. (2005). Structure and antitumor activities of the water-soluble polysaccharides from Ganoderma tsugae mycelium. Carbohyd. Polym. 59 385-392. 

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