Of DIVEMA

There are, however, many unsolved problems concerning toxicity, endocytic uptake and immunogenicity of DIVEMA. In order to learn more about the structure dependency of these properties, we sythesized some DIVEMA derivatives and investigated DIVEMA and the new derivatives with appropriate routine biological test systems. 

One disadvantage of DIVEMA is its relatively high toxicity which is mainly caused by high molecular weight fractions ( 7). In an attempt to lower the toxicity of DIVEMA, derivatives (3) and (4) were synthesized. 

Table II. Acute toxicity of DIVEMA and some derivatives...

Effects of DIVEMA and DIVEMA Derivatives on the Immune System. 

Mitogenic Activity of DIVEMA Derivatives. A first approach to the effects of a compound on the immune system is to test its ability to stimulate lymphocyte proliteration. An appropriate test is to measure the incorporation of 3H-thymidine into DNA of dividing cells ... 

Schultz eT"al. (21, 22) found that macrophages of DIVEMA-treated mice iFFibited tumour cell proliferation in vitro this means that DIVEMA activates macrophages. The authors did not find cytotoxic factors in the supernatant of these macrophage cultures. 

Release of cytotoxic factors into the supernatant was tested by adding the supernatant of DIVEMA-treated macrophages to cultures of defined amounts of P815 tumour cells and measuring LDH from lysed tumour cells after 24 hr. of incubation. 

IZU Izummdov, V.A., Gorshkova, M.Yu., and Volkova, I.F., Controlled phase separations in solutions of soluble polyelectrolyte complex of DIVEMA (copolymer of divinyl ether and maleic anhydride), Eur. Polym. J., 41, 1251,2005. 

Divinyl ether-maleic anhydride [DIVEMA] is a water-soluble polymer that has antitumor activity against various types of tumors. The biological activities of DIVEMA are due to its ability to activate immunocompetent macrophages and natural killer cells. DIVEMA may be used as a drug carrier for superoxide... 

The antiviral and antitumor activity as well as the lymphocyte activation and modulation of the sensitivity to bacterid endotoxine are biological effects of DIVEMA based on the modification of the immunological responsiveness of the organism. Because of its antitumor activity, DIVEMA has been included under the code number NSC 46015 in a broad antitumor testing. Later it was found that the original NSC 46015 preparation was polydisperse and more narrow fractions were used It can be concluded from these studies that the activation of macrophages to kill the tumor cells is the predominant if not the only mechanism of antitumor activity of DIVEMA This is very probably true for many other synthetic polymers that... 

DIVEMA was the first synthetic polymer approved for clinical trials in cancer treatment, but initial tests in humans demonstrated unacceptable toxicity [27]. It was shown that the toxidty was due mainly to the molecular mass fractions with low molecular mass were inactive but nontoxic, while fractions with higher molecular mass were both active and toxic [14,16]. The clinical tests continued with a fraction of DIVEMA copolymer with relatively low molar mass (12000-15000 Da), named MVE-2, but it was proved not to be active [28,29]. The toxidty of the polymer was diminished by... 

The NCS was also modified with DIVEMA copolymer. The in-vivo toxicity of the resulting conjugate was reduced, but the EPR effect was not observed. This was explained by the hydrophilicity of DIVEMA that did not favor the binding with albumin which would increase the apparent size, as in the case of SMANCS [103]. Some efforts were also made in order to obtain a conjugate of tumor necrosis factor with DIVEMA copolymer [104]. In this case, several free amino groups of the protein need to be protected before the reaction with the maleic copolymer. In the in-vivo test, the conjugate had a much higher antitumor effect than the native tumor necrosis factor. 

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