DIVEMA toxicity

DIVEMA and some DIVEMA derivatives were synthesized and tested for toxicity and immunological behaviour. 

Toxicity can be varied by introducing different side groups into parent DIVEMA molecules by polymer analogous reactions. 

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...

None of the substances caused significant enzyme secretion by macrophages. Only the pyrrolidone derivative (3a) caused a slight increase of LDH with increasing dose of the polymer. This finding corresponds to the higher acute toxicity of (3b) as compared to unsubstituted DIVEMA derivative (1b). 

Figure 1 shows schematically how the experiment was done. All substances tested,(1c), (1d), (3a), (3b),(4a), (4b), caused increasing cytotoxic activity of the supernatant with increasing doses of the polymers. Though the absolute values of LDH-1iberation differ greatly from one experiment to another, this qualitative result is the same in all tests (VO. One typical diagram showing the dose dependency of supernatant mediated toxicity caused by polymer (3b) is shown in Fig. 2. Relatively low concentrations (50 - 100 pg/ml) were sufficient to cause substantial cytotoxicity. As far as we know, this is the first example of supernatant-mediated toxicity caused by DIVEMA.

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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