PHARMACEUTICAL AND BIOLOGICAL EVALUATIONS April 2017; Vol. 4 (Issue 2): 127-129. www.onlinepbe.com
ISSN 2394-0859
Short Communication
Drug resistance: important criteria for cancer drug development Radhika Chelamalla Centre for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad-500085, Telangana, India
*For correspondence Dr. Radhika Chelamalla, Centre for Pharmaceutical Sciences, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad500085, Telangana, India. Email:
[email protected]
ABSTRACT
Received: 24 February 2017 Accepted: 23 March 2017
Keywords: Drug resistance, Cancer drug development, Clinical outcomes
Molecularly targeted agents light at end of tunnel to resolve therapeutics by drawing together morbidity and mortality in patients by the whole of cancer. However, still an urgent has a passion for preferably effective anticancer compounds, state-of-the-art preclinical abused substance evaluations largely overlook to answer a need the demand. New preclinical strategies, including the review of with all the extras mouse models and co-clinical design designs, are for used to boost the predictive price tag of animal-based translational aries research. Here, we saw in a new light the society of born with a silver spoon preclinical antineoplastic agents, their associated limitations, and arbitrary methods to feel in one bones clinical outcomes.
cancers. As per data of the National Cancer Registry Programme of the India Council of Medical Research (ICMR), the estimated mortality rate due to cancer saw an increase of six per cent approximately between 2012 and 2014. In its projection, the Indian Council of Medical Research (ICMR) said in 2016 the total number of new cancer cases is expected to be around 14.5 lakh and the figure is likely to reach nearly 17.3 lakh new cases in 2020. In women the lung, breast, colon and rectum are the cancer sites most frequently leading to death.
Cancer is one of the major life threatening diseases and it is characterized by uncontrolled growth of cells, which can invade and spread to distant sites of the body. After the treatment of tuberculosis, cancer is one of the major human killers. There are more than 100 types of cancer, including breast cancer, skin cancer, lung cancer, colon cancer, prostate cancer, and lymphoma.1 According to WHO report, 14 million people were diagnosed with cancer and 8 million died of the disease worldwide in 2012. It is expected that annual cases will rise from 14 million in 2012 to 22 which in the next 2 decades. According to the International Agency for Research on Cancer (IARC), a World Health Organization entity, India had 1.8 million people living with cancer (within five years of diagnosis) in 2012.2 During that year, about a million new cases were recorded, while about 683,000 deaths due to cancer were registered. According to recent statistics from the American Cancer Society, the top three cancers in men are prostate, colorectal and lung
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In this era, management and treatment of cancer is a challenge to all researchers and healthcare personnel. The management of cancer procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as
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DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors.
to overcome the drug resistance problem and give patient better chance to survive longer with fewer side effects. Recent research has focused to synthesize heterocyclic scaffolds having anticancer activity due to the synergistic effect of the fused compounds to overcome the resistance.
About 45% of all cancers are resistant to chemotherapy and the main hurdle to treating resistant cancer cells is the development of multi drug resistance (MDR). Development of resistant to chemotherapy is a major problem in oncology. Failure of cancer therapy is commonly attributed to pre-existing resistant mutants already present prior to treatment or can initially responsive but develops resistance. The various mechanisms of MDR are over expression of ATP Binding Cassette efflux transporters, decrease in drug uptake by solute carriers, inhibition of apoptosis as a result of mutated cell cycle proteins such as p53, altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered tareget enzyme, decreased drug activation, increased drug degradation due to altered expression of drug-metabolising enzymes, subcellular redistribution, drug interaction, increase in DNA repair, inactivation of chemotherapeutic drugs by metabolic enzymes.3-5
During the last two decades, several heterocyclic derivatives have been developed as chemotherapeutic agents and have found wide clinical applications. Attempts to overcome resistance mainly involve the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors and the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in delaying onset of resistance.7-8 Recent research has focused to target indolamine-2,3dioxigenase, ATP Binding Cassette transporters as a most compelling target for cancer treatment as this approach can increase clinical efficacy, cost effectiveness, tolerability and targeted treatment strategy.
Thus, drug resistance is a big challenge facing the survival of cancer patients. Combination of drugs could synergistically reduce tumor growth and the development of drug resistance compared to the use of each single agent. The availability of such a combination approach could bring an effective treatment for the two-third of cancer patients who lose their life too soon due to the development of drug resistance. However, some combinations can be so toxic that they have to be used at lower doses that may not be effective against the cancer. Some anticancer drugs like Cyclophosphamide become ineffective in progressive breast cancer because of drug resistance. New developmental agents with improved specificity for tumour cells, such as Trastuzumab & Ixabepilone with low susceptibility to tumour resistance, have provided new hope for effective treatment of breast cancer by targeted therapy.6
Thus the discovery of new anticancer agents with promising activity and high therapeutic index is an urgent need. A number of new drugs are in the market or in development stage which surely will make a difference in averting cancer. We are on our way to develop new drug or strategy but at the same time we also need to concentrate on the adverse effect, risk factor, pathophysiological mechanism and drug resistance to confer best remedy to the patient suffering from cancer and its complications. Funding: No funding sources Conflict of interest: None declared
References 1. Borchardt JK. The beginnings of drug therapy: Ancient mesopotamian medicine. Drug News Perspect. 2002;15:187–92. 2. Available at http://www.who.int/mediacentre/factsheets/fs297/en. Accessed on 15 January 2017. 3. Luqmani YA. Mechanisms of Drug Resistance in Cancer Chemotherapy. Med Princ Pract. 2005;14 Suppl 1:35–48.
Therefore searching and evaluation of novel compounds as potential anticancer agents with selective and less toxic is still one of the most important issues of scientific researchers. For decades, numerous efforts have been made in the area of cancer therapy and related diagnostics. In spite of the promising progress that has been achieved, certain challenges still remain. Research in drug discovery and design with new chemistry structure or mechanism of action is critical
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4. Housman G, Byler S, Heerboth S. Drug Resistance in Cancer: An Overview. Cancers. 2014;6:1769-92. 5. Michael M. Gottesman. Mechanisms of cancer drug resistance. Annu Rev Med. 2002;53:615–27. 6. Helen M. Coley Mechanisms and strategies to overcome. Mechanisms and strategies to overcome chemotherapy resistance in
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metastatic breast cancer. Cancer Treatment Reviews. 2008;34(4):378-90. 7. Zahreddine H, Borden KL. Mechanisms and insights into drug resistance in cancer. Front Pharmacol. 2013;(4):28. 8. Tito Fojo. Cancer, DNA Repair Mechanisms, and Resistance to Chemotherapy. J Natl Cancer Inst. 2001;93(19):1434-6.
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