Endotoxins antitumor activity

A link between bacteria and tumor therapy was found early, at the beginning of the XVIII century [10]. By the end of the XIX century, Coley [11] developed a treatment for cancer with a mixture of bacterial toxins. In 1943 Shear and Turner [4] found that the antitumor effect of Coley s toxin was due to endotoxins, and after several decades it was shown that the biological activity of LPS was due to the lipid A [5]. We investigated the structures of lipids A with regard to their antitumor activities [12], finding that the optimum in vivo activity is obtained with diglucosamines acylated by 3 long chain fatty acids. 

Parr et al. [61] showed that lipid A has the same antitumoral effect as whole endotoxin preparations on murine L5178Y lymphoma. The effects of LPS and synthetic lipid A treatments were compared by Shimizu et al. [158-161] on Meth A fibrosarcoma in BALB/c mouse. The antitumoral activity of different lipids A has also been investigated. Ribi et al. [162] used an extract from S. typhimurium containing lipid A, which when injected directly into hepatocarcinoma line 10 tumors in guinea pigs shows an antitumoral effect. This activity is attributed to a monophosphoryl diglucosamine derivative of lipid A [163], Synthetic lipid A analogs also proved to be active in this system [164], as well as... 

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)-... 

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... 

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. 

Macrophage Activation - The role of macrophages in tumor rejection is being actively investigated. Certain compounds which exhibit antitumor activity has been shown to act via the macrophage, probably through macrophage-mediated cytotoxicity. include endotoxin and double... 

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