Searching for new TNF-alpha analogs having potential application in cancer therapy.
Two new TNF-alpha analogs were prepared and tested for their anti-tumor activity on fibrosarcoma SA-1 tumor model in vivo. In analog LK-801 two histidines (His107His108) were introduced into the surface loop thus enabling efficient purification by metal-affinity chromatography. This analog showed less side effects and can serve as a lead compound to look for other useful mutations. Another analog LK-802 was designed by introduction of additional pair of mutations (Cys95Cys148) into LK-801 in order to prepare disulfide linked TNF trimers. Cytotoxicity on mouse cell line L929 was comparable to TNF-alpha, but effect on tumor growth was quite reduced. Pharmacokinetic study revealed that serum levels of LK-802 were quite low in comparison to native TNF-alpha. This at least partially explains why anti-tumor activity of LK-802 is reduced and also illustrates the problems in designing the analogs with desired in vivo biological properties.
Menart
V
V
Lek d.d., Research and Development, Ljubljana, Slovenia.
Kus
B
B
Novaković
S
S
Sersa
G
G
Gaberc-Porekar
V
V
Harb
V
V
Milicić
S
S
Stalc
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D005354:Fibrosarcoma / Q000188:drug therapy; D006801:Humans; D051379:Mice; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha