ABSTRACT
A serious drawback of tumor necrosis factor alpha (TNF) as a clinical antitumor agent is that it also has hypotensive activity. To overcome this problem, derivatives of its sister cytokine lymphotoxin (TNF-beta or LT) were prepared. One of them, mutein 2 (Mut2) has a deletion of amino acids 1-7 but contains substituted amino acids, Met-Phe-Pro at positions 8-10 of the mature human LT. This mutein has no hypotensive activity at the maximum dose (10 mg/kg) tested on rats. In contrast, a much lower dose (1 mg/kg) of TNF and LT caused a significant blood pressure drop. In vivo studies revealed that Mut2 was more effective than TNF or LT against MethA (a mouse tumor line) as judged by the therapeutic ratio [calculated as LD50 (dose that kills 50% of the animals)/ED50 (dose that reduces the tumor size by 50%)]. With five other different mouse tumors and two different human tumors, Mut2 was also effective and the effectiveness was comparable or superior to that of TNF or LT. These results suggest the possibility that this derivative may be usable as a clinical antitumor agent without the serious side effects associated with TNF.
Subject(s)
Antineoplastic Agents/pharmacology , Hypotension/chemically induced , Lymphotoxin-alpha/pharmacology , Recombinant Proteins , Tumor Necrosis Factor-alpha/pharmacology , Animals , Humans , Lymphotoxin-alpha/adverse effects , Male , Mice , Mice, Nude , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Tumor Cells, Cultured , Tumor Necrosis Factor-alpha/adverse effectsABSTRACT
MS-681a, b, c and d are new inhibitors of myosin light chain kinase produced by Myrothecium sp. They are novel octapeptides containing alpha-alkyl-alpha-amino acids and a polyamine moiety. The structures were determined by NMR and FAB-MS/MS spectral analyses of the intact peptides. Their absolute configurations were elucidated by GC analysis on a chiral column of the constituent amino acids and by chemical synthesis of the polyamine moieties.
