Lipid antitumor activity

Storm, G., Roerdink, F. H., Steerenberg, P. A., De jong, W. H., and Crommelin, D. J. A. (1987). Influence of lipid composition on the antitumor activity exerted by doxorubicin-containing liposomes in a rat solid tumor model, Cancer Res., 47, 3366-3372. 

Colquhoun and Schumacher [98] have shown that y-linolcnic acid and eicosapentaenoic acid, which inhibit Walker tumor growth in vivo, decreased proliferation and apoptotic index in these cells. Development of apoptosis was characterized by the enhancement of the formation of reactive oxygen species and products of lipid peroxidation and was accompanied by a decrease in the activities of mitochondrial complexes I, III, and IV, and the release of cytochrome c and caspase 3-like activation of DNA fragmentation. Earlier, a similar apoptotic mechanism of antitumor activity has been shown for the flavonoid quercetin [99], Kamp et al. [100] suggested that the asbestos-induced apoptosis in alveolar epithelial cells was mediated by iron-derived oxygen species, although authors did not hypothesize about the nature of these species (hydroxyl radicals, hydrogen peroxide, or iron complexes ). 

Dow SW, et al. Lipid-DNA complexes induce potent activation of innate immune responses and antitumor activity when administered intravenously. J Immunol 1999 163 1552. 

ANTITUMORAL ACTIVITY OF LIPIDS A STUDIES IN ANIMAL MODELS AND CANCER... 

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. 

Animal models permit the investigation of the antitumoral effect of lipids A and LPS [57], We will first consider the acute effects observed after the first injection of lipids A or LPS. In each case, their relevance to an antitumoral activity will be discussed. 

However, we showed that no correlation exists between the capacity of LPS and lipids A to activate macrophages from BDIX rats in vitro and their in vivo antitumoral activity to PROb tumors except for EL1-P production [12,82,83]. In any case, the importance of macrophages has been emphasized because they are the main producer of TNF-a in response to LPS. 

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... 

M. Lohmeyer and P. Workman. Growth arrest vs direct cytotoxicity and the importance of molecular-stmcture for the in-vitro antitumor-activity of ether lipids. Br. J. Cancer, 1995, 72, 277-286. 

New folate antagonists have been identified that are better substrates for the reduced folate carrier and appear to have significant advantages in clinical chemotherapy (see pemetrexed below). In efforts to bypass the obligatory membrane transport system and to facilitate penetration of the blood—brain barrier, lipid-soluble folate antagonists also have been synthesized. Trime-trexate (NEVTREXIN) has modest antitumor activity, primarily in combination with leucovorin rescue. However, it is beneficial in the treatment Pneumocystis jiroveci pneumonia, where leucovorin provides differential rescue of the host but not the parasite. 

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