Platelet‐derived endothelial cell growth factor Pharmacokinetics, organ distribution and degradation after intravenous administration in rats

Abstract

Platelet-denved endothelial cell growth factor (PD-ECGF) stimulaten chcmotaxts of endothehal cells in wtro and has angiogenic acttvity m vtvo. Recenti2¢ PD-ECGF was shown to have thymidine phosphorylase activity. In order to ~tudy po5,~tble thcral~ntte appheation~ of PD-I:COF we used a rat model to determine it~ pharmacokinettc~ and tt~sue dtstnbuttoa after intravenou~ injection.[~2~I]PD-ECGF dtsappeared from the plasma in a btphasic manner, with estimated distribution and ehmmation half-hves of 17 rain and 7 h, respectively. PD-ECGF was metabolized tn the liver, excreted via the bde, and not accumulat~ an any organ system. The stability and long half-hfe in the cireulatton, together wah the specificity for endothelial cell.~, suggest that PD-ECGF may be useful as a therapeutic agent to stimulate re-endolhelialization m vtvo, or, in vtcw of its thym~dine phosphoryla~e activity, in chemotherapy, by decrcasmg the pool of available thymidine.

Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE): Biochemical Features and Therapeutic Approaches

“…It is not expressed or present at low levels in skeletal muscle although this tissue is clearly affected in MNGIE (Yoshimura et al 1990;Waltenberger et al 1992;Eccleston et al 1995;Fox et al 1995, Matsukawa et al 1996Focher and Spadari 2001). TP expression and activity are increased and correlate with neoplastic growth in some tumors (Yoshimura et al 1990;Griffiths and Stratford 1997;Focher and Spadari 2001).…”

“…Skeletal muscle is affected in MNGIE patients, but this tissue expresses little or no TP (Yoshimura et al 1990;Waltenberger et al 1992;Fox et al 1995;Matsukawa et al 1996), which initially raised the question of why one tissue that does not express normally the protein at high levels is affected by mutations in this gene (muscle paradox), (Nishino et al 1999). The systemic accumulation of dThd and dUrd in MNGIE patients provided an explanation to this apparent paradox: skeletal muscle is affected, not because its TP dysfunction, but rather due to the toxic effects of accumulated dThd and dUrd.…”

Liver as a Source for Thymidine Phosphorylase Replacement in Mitochondrial Neurogastrointestinal Encephalomyopathy

“…Normal buffy coats showed TP levels similar to the duodenal mucosa, but was not detectable in MNGIE buffy coats (used as negative control). Finally, TP immunoreactivity was undetectable in skeletal muscle, a finding that has previously been referred to as the ‘muscle paradox’ since this tissue is known to be a target of disease in MNGIE patients but does not contain TP [29], [30], [37], [38]. The explanation for the ‘muscle paradox’ remains unclear and this intriguing topic clearly requires further study.…”

Thymidine phosphorylase mutations cause instability of mitochondrial DNA

“…Thymidine phosphorylase is expressed in most human tissues including: gastrointestinal system, brain, peripheral nerve, spleen, bladder and lung, but is not expressed in muscle, kidney, gall bladder, aorta, and fat (Yoshimura et al, 1990;Waltenberger et al, 1992;Fox et al, 1995;Matsukawa et al, 1996). This tissue distribution expression of TP is consistent with the major clinical features of MNGIE; however, skeletal muscle paradoxically lacks TP activity and is usually affected in MNGIE based on the observation of ragged-red fibers, COX deficiency, and mtDNA alterations in this tissue.…”