Since muramyl dipeptide (MDP) was recognized as a potent monocyte/macrophage activating agent, many MDP analogues were synthesized and tested for their ability to augment the host immune defence system against neoplasms. This study was performed to determine whether the newly synthesized desmuramyl N-acyl dipeptides LK 409 and LK 410 were also capable of affecting the immune system. For this purpose, the peritoneal macrophages were incubated in vitro with these two agents and TNF-alpha production was measured. In addition, the effect of LK 409 and LK 410 on TNF-alpha and IL-1 RNA levels in in vivo stimulated macrophages was determined by quantitative polymerase chain reaction (RT-PCR). None of the LK 409 and LK 410 concentrations tested were able to render macrophages in vitro to excrete a detectable amount of TNF-alpha in the supernatant fluid. However, the TNF-alpha and IL-1 RNA levels in macrophages of in vivo treated mice (C57Bl/6) were increased in comparison to mock-treated mice. The results indicate that LK 409 and LK 410 are capable of inducing an increase in TNF-alpha and IL-1 RNA levels, yet in vitro TNF-alpha production remains under detectable levels (40 U/ml).

01 Dec 1992·Molecular biotherapy

Antitumor effect of recombinant human tumor necrosis factor-alpha analog combined with desmuramyl dipeptides LK-409 or LK-410 on sarcoma in mice.

Article

Author: Sersa, G ; Stalc, A ; Novakovic, S

Antitumor effect of recombinant human tumor necrosis factor (TNF)-alpha lacking one to three amino acids from the N terminal part (TNFNv3) was tested for its antitumor effect on subcutaneous fibrosarcoma SA-1 tumors. Peritumoral treatment with 5 x 10(4) U TNFNv3 three times every second day significantly delayed tumor growth. Treatment with 10 times higher dose (5 x 10(5) U) produced 6.0 +/- 1.0 days tumor growth delay, but had side effects such as weight loss. The two new desmuramyl N-acyl dipeptides, LK-409 and LK-410, also exhibited such effect; however, the tumor growth delay was barely significant. The treatment was performed with two concentrations (2.5 micrograms and 25.0 micrograms) applied intraperitoneally for 5 consecutive days, without a dose-dependent effect. Combined treatment with TNFNv3 and desmuramyl dipeptides augmented the antitumor effect of treatments. The effect was additive and significant in the combination of 2.5 micrograms LK-410 with 5 x 10(5) U TNFNv3. LK-410 treatment also reduced the side effects of TNFNv3. The results indicate that combined treatment with both biological response modifiers is effective in tumor treatment.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Discovery	SI	Lek Pharmaceuticals dd	-

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