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      Hybrid Drugs—A Strategy for Overcoming Anticancer Drug Resistance?

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          Abstract

          Despite enormous progress in the treatment of many malignancies, the development of cancer resistance is still an important reason for cancer chemotherapy failure. Increasing knowledge of cancers’ molecular complexity and mechanisms of their resistance to anticancer drugs, as well as extensive clinical experience, indicate that an effective fight against cancer requires a multidimensional approach. Multi-target chemotherapy may be achieved using drugs combination, co-delivery of medicines, or designing hybrid drugs. Hybrid drugs simultaneously targeting many points of signaling networks and various structures within a cancer cell have been extensively explored in recent years. The single hybrid agent can modulate multiple targets involved in cancer cell proliferation, possesses a simpler pharmacokinetic profile to reduce the possibility of drug interactions occurrence, and facilitates the process of drug development. Moreover, a single medication is expected to enhance patient compliance due to a less complicated treatment regimen, as well as a diminished number of adverse reactions and toxicity in comparison to a combination of drugs. As a consequence, many efforts have been made to design hybrid molecules of different chemical structures and functions as a means to circumvent drug resistance. The enormous number of studies in this field encouraged us to review the available literature and present selected research results highlighting the possible role of hybrid drugs in overcoming cancer drug resistance.

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          Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings

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            Molecular properties that influence the oral bioavailability of drug candidates.

            Oral bioavailability measurements in rats for over 1100 drug candidates studied at SmithKline Beecham Pharmaceuticals (now GlaxoSmithKline) have allowed us to analyze the relative importance of molecular properties considered to influence that drug property. Reduced molecular flexibility, as measured by the number of rotatable bonds, and low polar surface area or total hydrogen bond count (sum of donors and acceptors) are found to be important predictors of good oral bioavailability, independent of molecular weight. That on average both the number of rotatable bonds and polar surface area or hydrogen bond count tend to increase with molecular weight may in part explain the success of the molecular weight parameter in predicting oral bioavailability. The commonly applied molecular weight cutoff at 500 does not itself significantly separate compounds with poor oral bioavailability from those with acceptable values in this extensive data set. Our observations suggest that compounds which meet only the two criteria of (1) 10 or fewer rotatable bonds and (2) polar surface area equal to or less than 140 A(2) (or 12 or fewer H-bond donors and acceptors) will have a high probability of good oral bioavailability in the rat. Data sets for the artificial membrane permeation rate and for clearance in the rat were also examined. Reduced polar surface area correlates better with increased permeation rate than does lipophilicity (C log P), and increased rotatable bond count has a negative effect on the permeation rate. A threshold permeation rate is a prerequisite of oral bioavailability. The rotatable bond count does not correlate with the data examined here for the in vivo clearance rate in the rat.
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              Cancer drug resistance: an evolving paradigm.

              Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Molecules
                Molecules
                molecules
                Molecules
                MDPI
                1420-3049
                29 April 2021
                May 2021
                : 26
                : 9
                : 2601
                Affiliations
                [1 ]Department of Hospital Pharmacy, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego Street, 90-151 Lodz, Poland
                [2 ]Department of Pharmacology and Toxicology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; anna.wiktorowska-owczarek@ 123456umed.lodz.pl
                [3 ]Department of Community Pharmacy, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynskiego Street, 90-151 Lodz, Poland; andrzej.stanczak@ 123456umed.lodz.pl
                Author notes
                Author information
                https://orcid.org/0000-0001-7562-8933
                https://orcid.org/0000-0003-3452-5748
                Article
                molecules-26-02601
                10.3390/molecules26092601
                8124695
                33946916
                80e9e454-16ff-42a5-a668-dbb02bee2ae5
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 30 March 2021
                : 26 April 2021
                Categories
                Review

                hybrid drug,conjugate,cancer,drug resistance,overcoming anticancer drug resistance

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