Inhibition of systemic TNF-alpha cytotoxicity in cancer patients by D-peptidoglycan
The current study was designed to investigate direct inhibitory effects of N-acetylglucosaminyl-muramyldipeptide (GMDP) over the cytotoxic nature of TNF-α. A lactate dehydrogenase (LDH) assay of the inhibition of TNF-α cytotoxicity was donein vitro on the following cell lines: A549 (human lung carcinoma cells), A431 (human breast cancer cells) and L929 (mouse breast cancer cells). In a double-blind placebo-controlled trial, cancer patients with an elevated activity of all five LDH isoensymes were randomized to receive either a GMDP solution or a placebo; 63 patients were evaluated every third day for the mean daily number of episodes of nausea or vomiting, changes in clinical status, cell blood count and blood chemistry. A 95% inhibition of LDH release was noticed on A549 cells. Other cell lines were less sensitive to GMDP, with an observed 72% dose-dependent reduction in LDH activity.In vivo, LDH activity was decreased by 41% (+/−4%) (mean +/−SD) in all 21 subjects who were given 0.5–1.0 mg of GMDP daily. A lowering of LDH activity by 73.4% (+/−4%) was observed in 23 patients who received GMDP at a dosage of 1.5 mg/kg daily. Correspondingly, a 10% (+/−2%) increase in LDH activity was noticed in 19 patients who were given a placebo (P<0.01). During the follow-up period, the overall clinical condition of all patients treated with GMDP was improved. No side effects were observed. In nine patients who experienced nausea from tumor toxicity before treatment, the symptom subsided. In parallel, an extremely beneficial effect on lipids metabolism was noticed in all patients with elevated cholesterol and trigliceride levels. A dietary supplementation of GMDP has been shown to reduce systemic TNF-α cytotoxicity during tumor shock.
KeywordsTNF-α LDH N-acetyl-glucosaminyl-muramyldipeptide (GMDP) tumor shock GGTP
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- 3.Heinig Jet al. Semiquantitative determination of IL-1 alpha, TNF-alpha, PDGF-A, PDGF-B, and PDGF-receptor in term human placenta using polymerase chain reaction (PCR).Gynecol 1993;115: 317–322.Google Scholar
- 4.Recdal O, Osterud B, Svendsen JS, Winberg JO. Evidence for exclusive role of the p55 tumor necrosis factor (TNF) receptor in mediating the TNF-induced collagenase expression by human dermal fibroblasts.J Invest Dermatol 1996;96: 243–249.Google Scholar
- 12.Jacobs CA, Smith CA. Methods of lowering active TNF-alpha levels in mammals using tumor necrosis factor receptor. US patent 5605690 1997.Google Scholar
- 17.Slesarev VL, Efimov VA, Oraevsky AV, Slesarev AI. Nonspecific vaccination by D-aminoacid containing compounds: International patent application WO 08/510,737, 1997.Google Scholar
- 18.Slesarev VI. US patent application 08/757,477, 1996.Google Scholar
- 19.Ovchinnikov Yuet al. Glycopeptides and methods for preparing same. US patent 4,395,399, 1983.Google Scholar
- 20.Andronova T, Ivanov V. The structure and immunomodulating function of glucosaminylmuramyl peptides.Sov Med Rev Immunol 1989;4: 1–63.Google Scholar
- 24.Aston R. Muramyl compounds for treatment of septic shock. US patent 5506204, 1996.Google Scholar
- 25.Preketes APet al. Immunological activity and serum CEA levels following oral administration of muramyl dipeptide (GMDP) to patients with advanced colorectal cancer.Surg Res Comm 1996;18: 137–146.Google Scholar