New TNF-alpha analogues: a powerful but less toxic biological tool against tumours.
Our approach to the modification of recombinant human tumour necrosis factor alpha (rhTNF-alpha) comprised changes in flexible loop regions on the surface of the TNF molecule. Using this approach, two different rhTNF-alpha analogues LK 801 and LK 805 were synthesized and tested for their ability to affect the growth of Sa-1 tumour cells. Results obtained in vitro indicate that neither rhTNF-alpha nor its analogues have a direct cytotoxic effect. In vivo experiments were performed on subcutaneous Sa-1 tumours in A/J mice, where the antitumour effect and the toxic side effects of the cytokines were followed. There was no significant difference between growth delay of tumours in animals treated with native rhTNF-alpha and in animals treated with one of the analogues. On the contrary, the LD50 for rhTNF-alpha was 29.1 microg, for LK 801 59.3 microg, and for LK 805 even 66.1 microg, indicating that LK 801 and especially LK 805 were significantly better tolerated. The results confirm that the rhTNF-alpha molecule has been successfully modified resulting in two new analogues with a potent antitumour activity and much lower systemic toxicity. A particularly low systemic toxicity and a strong antitumour effect were observed after treatment with LK 805 suggesting that this analogue merits further investigation in pre-clinical and clinical trials.
Novaković
S
S
Institute of Oncology, Zaloska 2, Ljubljana, 1105, Slovenia.
Menart
V
V
Gaberc-Porekar
V
V
Stalc
A
A
Sersa
G
G
Cemazar
M
M
Jezersek
B
B
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D002455:Cell Division; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D051379:Mice; D008805:Mice, Inbred A; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha