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Cancer Treatment Using Peptides: Current Therapies and Future Prospects

Promulgator:shinepeptide   Send date:2013-03-09 14:13 Visitor:

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.

1. Introduction

Mortality from cancer is about to surpass that from cardiovascular diseases in near future. About 7 million people die from cancer-related cases per year, and it is estimated that there will be more than 16 million new cancer cases every year by 2020 [1, 2]. Cancer is characterized by uncontrolled division of cells and the ability of these cells to invade other tissues leading to the formation of tumor mass, vascularization, and metastasis (spread of cancer to other parts of the body) [3]. Though angiogenesis (growth of new blood vessels from preexisting vessels) is a normal and vital process in growth and development, it is also a fundamental step in the transition of tumors from a dormant state to a malignant one [4]. Chemotherapy is one of the major approaches to treat cancer by delivering a cytotoxic agent to the cancer cells. The main problem with the conventional chemotherapy is the inability to deliver the correct amount of drug directly to cancer cells without affecting normal cells [5]. Drug resistance, altered biodistribution, biotransformation, and drug clearance are also common problems [5]. Targeted chemotherapy and drug delivery techniques are emerging as a powerful method to circumvent such problems [6–10]. This will allow the selective and effective localization of drugs at predefined targets (e.g., overexpressed receptors in cancer) while restricting its access to normal cell thus maximizing therapeutic index and reducing toxicity.

Discovery of several protein/peptide receptors and tumor-related peptides and proteins is expected to create a “new wave” of more effective and selective anticancer drugs in the future, capturing the large share of the cancer therapeutic market [6, 8, 11]. The “biologics” treatment option against cancer includes the use of proteins, monoclonal antibodies, and peptides. The monoclonal antibodies (mAbs) and large protein ligands have two major limitations compared to peptides: poor delivery to tumors due to their large size and dose-limiting toxicity to the liver and bone marrow due to nonspecific uptake into the reticuloendothelial system. The use of such macromolecules has therefore been restricted to either vascular targets present on the luminal side of tumor vessel endothelium or hematological malignancies [12–17]. Peptides possess many advantages, such as small size, ease of synthesis and modification, tumor-penetrating ability, and good biocompatibility [18, 19]. Peptide degradation by proteolysis can be prevented by chemical modifications such as incorporation of D-amino acids or cyclization [18].

Over the years peptides have been evolved as promising therapeutic agents in the treatment of cancer, diabetes, and cardiovascular diseases, and application of peptides in a variety of other therapeutic areas is growing rapidly. Currently there are about 60 approved peptide drugs in the market generating an annual sale of more than $13 billion [18]. Out of four peptide drugs in the market which have reached global sales over $1 billion, three peptides are used in treating cancer directly or in the treatment of episodes associated with certain tumors (leuprolide, goserelin, and octreotide). The number of peptide drugs entering clinical trials is increasing steadily; it was 1.2 per year in the 1970s, 4.6 per year in the 1980s, 9.7 per year in the 1990s, and 16.8 per in 2000s [19]. There are several hundred peptide candidates in the clinic and preclinic development. From 2000 onwards, peptides entering clinical study were most frequently for indications of cancer (18%) and metabolic disorders (17%) [20].

This paper focuses on different strategies of employing peptides in cancer treatment and management. A special emphasis is given to current peptide drugs available in the market for treating cancer and also peptide candidates in clinical and preclinical stages of development. Peptides can be utilized in a number of different ways in treating cancer [8–10, 19]. This includes using peptides directly as drugs (e.g., as angiogenesis inhibitors), tumor targeting agents that carry cytotoxic drugs and radionuclides (targeted chemotherapy and radiation therapy), hormones, and vaccines. Different possible cancer treatment options using peptides are summarized in Figure 1. Due to the ability to bind to different receptors and also being part of several biochemical pathways, peptides act as potential diagnostic tool and biomarkers in cancer progression. Out of these different possibilities, peptide drugs currently available in the market come from peptide hormone therapy and tumor targeting agents carrying radionuclides (peptide-receptor radio nuclide therapy and imaging). Exceptions to these are two short chain peptide-related drugs, bortezomib and mifamurtide [21, 22]. There is a tremendous progress in other areas such as peptide-vaccine development and peptide angiogenesis inhibitors, and several clinical trials are underway which is expected to bear fruit in near future providing better options to millions of cancer patients.