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Cancer Treatment Using Peptides: Current Therapies and Future Prospects

发布者:shinepeptide   发布时间:2013-03-09 13:57 浏览次数:

This paper discusses the role of peptides in cancer therapy with special emphasis on peptide drugs which are already approved and those in clinical trials. The potential of peptides in cancer treatment is evident from a variety of different strategies that are available to address the progression of tumor growth and propagation of the disease. Use of peptides that can directly target cancer cells without affecting normal cells (targeted therapy) is evolving as an alternate strategy to conventional chemotherapy. Peptide can be utilized directly as a cytotoxic agent through various mechanisms or can act as a carrier of cytotoxic agents and radioisotopes by specifically targeting cancer cells. Peptide-based hormonal therapy has been extensively studied and utilized for the treatment of breast and prostate cancers. Tremendous amount of clinical data is currently available attesting to the efficiency of peptide-based cancer vaccines. Combination therapy is emerging as an important strategy to achieve synergistic effects in fighting cancer as a single method alone may not be efficient enough to yield positive results. Combining immunotherapy with conventional therapies such as radiation and chemotherapy or combining an anticancer peptide with a nonpeptidic cytotoxic drug is an example of this emerging field.

Bortezomib is the first therapeutic proteasome inhibitor to be tested in humans [21, 145, 146]. It is approved in the USA for treating relapsed multiple myeloma and mantle cell lymphoma (2003). In multiple myeloma, complete clinical responses have been obtained in patients with otherwise refractory or rapidly advancing disease. The drug is an N-protected dipeptide and can be written as Pyz-Phe-boroLeu, which stands for pyrazinoic acid, phenylalanine, and leucine with a boronic acid instead of a carboxylic acid. Mifamurtide (Mepact) is a drug against osteosarcoma, which is lethal in about a third of cases [147]. The drug was approved in Europe in March 2009 and is not currently approved in the USA. Mifamurtide is a fully synthetic derivative of muramyl dipeptide (MDP) the smallest naturally occurring immune stimulatory component of cell walls from Mycobacterium species. The side chains of the molecule give it a longer elimination half-life than the natural substance. Being a phospholipid, it accumulates in the lipid bilayer of the liposomes in the infusion. It recognizes muramyl dipeptide and simulates a bacterial infection by binding to NOD2 (NOD2 is a pattern recognition receptor which is found in several kinds of white blood cells, mainly monocytes and macrophages) activating white cells [148]. This results in an increased production of TNF-α, interleukin 1, interleukin 6, interleukin 8, interleukin 12, and other cytokines, as well as ICAM-1. The activated white cells attack cancer cells, but not other cells. Brentuximab Vedotin, an antibody drug conjugate (ADS) approved in 2011, is a chimeric monoclonal antibody, brentuximab (which targets the cell-membrane protein CD30) linked to three to five units of the antimitotic agent monomethyl auristatin E. The linker here is a valine-citrulline dipeptide which is cleaved by cathepsin once the conjugate has entered a tumor cell. The antimitotic agent monomethyl auristatin E can be considered as a peptidomimetic [149, 150].