Chimeric toxins composed of transforming growth factor alpha fused to mutant forms of Pseudomonas exotoxin bind to the EGF receptor and kill cells bearing these receptors. In early experiments, the binding domain of Pseudomonas exotoxin was deleted and replaced with TGF alpha to make TGF alpha-PE40. This chimeric toxin required proteolytic processing within the target cell to be converted to its active form (Siegall et al. (1989) FASEB J. 3, 2647-2652). Subsequently, recombinant toxins that do not require proteolytic processing were constructed by inserting TGF alpha near the carboxyl terminus of domain III and deleting toxin residues up to the processing site at position 280. In addition, the carboxyl terminus of this toxin was converted from REDLK to KDEL to increase its activity. Recombinant toxins of this type, termed PE37/TGF alpha/KDEL, are about 100-fold more potent than TGF alpha-PE40. To determine if other sequences can be removed from such chimeric toxins to make a smaller molecule that can penetrate tissues better, we have carried out a deletion analysis of sequences present within domains II and Ib. We find that all of domain Ib and a portion of domain II can be deleted without significant loss of cytotoxic activity, but larger deletions extending further into domain II lose cytotoxic activity. We also find that inserting a small linking peptide (Gly)4Ser between residual sequences in domain II and domain III, in molecules with diminished cytotoxic activity, enhances cytotoxicity suggesting that one role of domain Ib is to prevent undesirable interactions between domains II and III.(ABSTRACT TRUNCATED AT 250 WORDS)

ADP Ribose Transferases↗

PubMedDate not supplied

Abdominal wound dehiscence in patients receiving long-term steroid treatment.

Steroids inhibit primary wound healing and delay the formation of granulation tissue, but it has been controversial whether long-term steroid treatment by itself increases the risk of abdominal wound dehiscence. The aim of this study was to determine whether the pre-operative dose and post-operative total dose of steroids influence abdominal wound dehiscence. Of 28 patients who had surgery while receiving long-term steroid treatment, seven had abdominal wound dehiscence and 21 did not have dehiscence. The two groups differed significantly in the post-operative dose of steroids (404.3 +/- 147.1 and 135.6 +/- 118.7 mg, respectively) and the duration of wound healing (57.3 +/- 18.0 and 12.4 +/- 3.8 days), but no other differences were found. Abdominal wound dehiscence may be influenced by the post-operative rather than the pre-operative steroid dose.

Adolescent↗

PubMedDate not supplied

[Studies on the abnormalities of glucuronide formation and of the related enzymes in tumor-bearing hosts].

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Animals↗