Pharmacological elements in clinical application of synthetic peptides

Abstract

The research carried out on the biological properties of synthetic peptides and the possibility of obtaining them in adequate amounts through the recombinant DNA technology allows their use as therapeutical agents. Procedures following the synthesis of peptides must be performed in order to verify their structure, conformation, immunogenicity and biological activity and to make them suitable for clinical applications. The size of synthetic peptides together with some modifications such as amidation, acetylation and sulfatation must be taken into consideration as they may have a significant impact on half-life, stability and biological activity. Endothelial, epithelial and enzymatic interference which may hinder the absorption of drugs must be evaluated in order to choose the most appropriate route of administration. The considerable bioavailability related to the intravenous route, the effectiveness of the circulation of the intramuscular route and the possibility of reaching specific targets by the intra-arterial route must also be taken into consideration. There is the possibility of applying transdermal therapeutic systems and transdermal iontophoresis only for peptides of low molecular weight. Among synthetic peptides provided with antianaemic activity, erythropoietin, growth factors and interleukin 3 must be mentioned because of their effectiveness both in optimal stimulation of melopoiesis after chemotherapy or bone-marrow transplantation and in the treatment of anaemia occurring during chronic renal failure. Furthermore, interferon alpha was shown to be one of the most used synthetic peptides provided with antiviral and antineoplastic activity. Remarkable results have been obtained in the treatment of chronic hepatitis C, haematological malignancies and some solid tumours. More recently, interleukin 2 has been tested in the treatment of melanoma and renal cancer, inducing a reasonable proportion of overall response rate. Finally, the antagonist of gonadotropin-releasing-hormone may be regarded as effective agent both in the treatment of prostate cancer and in the inhibition of luteinizing-hormone surges during controlled ovarian stimulation. Toxic side effects can be related to the administered dose as well as to metabolites derived from bacteria in which peptides have been synthesized.

Recent Progress in Immunotherapy for Malignant Glioma: Treatment Strategies and Results from Clinical Trials

“…This strategy, although highly effective at eradicating tumors in rodents, 96,97 has generally been of limited applicability in human cancers due to either issues of toxicity or subtherapeutic half-life. 98,99 For malignant brain tumors, the use of cytokine therapy must also take into account the privileged status of the central nervous system vis-à-vis the blood-brain barrier (BBB). Given these limitations, recent strategies employing cytokine therapy have evolved toward locoregional delivery paradigms that can circumvent the physiologic and pharmacokinetic barriers associated with earlier strategies.…”

Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer

“…The systemic use of recombinant cytokines in humans is, with limited exception, precluded by concerns of toxicity and inadequate half -life. 3,4 Additionally, systemic therapies fail to adequately address local factors in the tumor microenvironment that contribute to the regional immunosuppression associated with malignant brain tumors. An important therapeutic strategy that aims to address these concerns is in situ cytokine gene transfer, which circumvents the problems associated with peripheral toxicity and subtherapeutic protein half -life of systemically or locally administered recombinant cytokine.…”

“…The use of direct recombinant cytokine therapy, although highly effective at eradicating tumors in rodents, 1,2 is generally of limited applicability in human cancers either due to issues of toxicity or subtherapeutic protein half -life. 3,4 With particular regard to malignant glioma, the use of immunomodulatory cytokines must also take into account the partial immune privileged status of the central nervous system and the documented ability of brain tumors to actively suppress host immune function. 5 -7 There has, therefore, been increased interest in developing locoregional cytokine delivery paradigms for brain tumors, which are able to circumvent and /or undermine the physiochemical barriers to immune access associated with gliomas.…”

Synthesis and evaluation of new iRGD peptide analogs for tumor optical imaging

“…Both N-acetylation and C-amidation of protein and peptide termini have been used as effective approaches to improve the stability and biological activities for some peptides 22, 23. Although N-terminal acetylation and/or C-terminal amidation reduce the overall charge and the solubility of the peptide, they can increase the permeability of the peptides to cells for intracellular, in vivo assay or in vitro functional studies.…”