Mechanisms of Resistance to Antineoplastic Drugs
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
Cellular resistance to antineoplastic drugs can be classified into a number of different types, as shown in Table 1. In considering these mechanisms, it should be remembered that members of the same class of drug may share common transport processes, metabolism, and site of action. Because drug resistance may be due to alterations in one or more of these parameters, the cells which develop resistance to a particular drug will frequently be cross-resistant to other members of the same class of drug. However, this will generally not affect the sensitivity of the cells to other classes of cytotoxic drugs. For example, there are several different mechanisms whereby cells may develop resistance to the antifolate methotrexate (4-deoxy-4-amino-10-methyl folate, MTX). While MTX-resistant cells may be resistant to other antifolates, in general antifolate-resistant cells are not cross-resistance to anthracy-clines.4 Likewise, resistance to one alkylating agent may lead to cross-resistance to other agents in this class, but does not in general result in cross-resistance to other classes of antitumor agents.5 The exception to this dogma is the phenomenon of pleiotropic or “multidrug” resistance (MDR). In this phenotype, cells selected for resistance to one agent develop cross-resistance to a wide range of agents which differ markedly in structure and apparent mechanism of action. Because of the clinical implications of and growing interest in this phenomenon, the mechanisms associated with the development of MDR will be considered in some detail later in this review.
Clindamycin and Lincomycin
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Increased reports of resistance to the lincosamides over the last 10–15 years are an area of major concern. Several mechanisms of resistance to clindamycin have been recognized, including target site modification, production of drug-inactivating enzymes, and increased efflux of the drug. Clindamycin inhibits protein synthesis by binding to the 50S unit of the ribosome. Although structurally unrelated to the lincosamides, the macrolides, streptogramins, ketolides, and oxazolidinones bind to a site on the 50S ribosome nearly identical to the binding site for the lincosamides. As a result, resistance to one of these antimicrobials can be accompanied by cross-resistance to the others. This cross-resistance phenotype is commonly referred to as macrolide–lincosamide–streptogramin (MLS or MLSB), macrolide–lincosamide– streptogramin–ketolide (MLSK), or macrolide–lincosamide– streptogramin–ketolide–oxazolidinone (MLSKO) resistance (see also Chapter 59, Erythromycin). Cross-resistance is, however, not absolute, and its development depends on the mechanism of resistance. Ribosomal target modification confers MLS cross-resistance, but inactivating enzymes and efflux pumps are more antimicrobial specific (Leclercq, 2002; Roberts, 2004).
HIV Integrase Inhibitors
Satya Prakash Gupta in Cancer-Causing Viruses and Their Inhibitors, 2014
IN inhibitor drugs act selectively on HIV IN and have no risk of developing crossresistance against other classes of HIV inhibitor drugs. However, these inhibitors are still susceptible to developing drug-resistant mutant viral strains. There is also a high probability of cross-resistance against other mechanistically similar IN inhibitors. The studies discussed in this chapter show several examples where an inhibitor molecule has been found to act as a dual inhibitor and could be further optimized as a novel HIV inhibitor. Future efforts for developing mechanistically and structurally distinct next generation novel IN inhibitors, targeting the interaction between viral protein IN and host cellular cofactor protein LEDGF/p75 and/or acting as dual inhibitor inhibiting two or more steps during the integration process, seem to be the most important approach for addressing these challenges.
The dawn of precision medicine in HIV: state of the art of pharmacotherapy
Published in Expert Opinion on Pharmacotherapy, 2018
Ying Mu, Sunitha Kodidela, Yujie Wang, Santosh Kumar, Theodore J. Cory
In addition to host genetics, variations between HIV strains can also cause drug resistance. For example, mutations in reverse transcriptase can cause resistance to NRTIs (Q151M, M184V, and K65R) and NNRTIs (Y181C, Y188C, K103N, G190A, and V106A). Mutations in the viral protease enzymes (L90M, V82A, V82T, and V82F) can cause resistance to PIs as well. Furthermore, cross-resistance impairs the success of alternative regimens. For instance, if a patient receiving first generation NNRTIs develops resistance to it, they will be resistant to second generation of NNRTIs even if they never take it [82]. Conventionally, genotypic and phenotypic assays are employed to detect the presence of resistance mutations. Because phenotypic testing (PT) is expensive and time consuming, genotypic testing (GT) is most commonly utilized in identifying resistance strains.
Clinical utility of emerging biomarkers in prostate cancer liquid biopsies
Published in Expert Review of Molecular Diagnostics, 2020
Emmy Boerrigter, Levi N. Groen, Nielka P. Van Erp, Gerald W. Verhaegh, Jack A. Schalken
Prostate cancer (PCa) is the most common malignancy in men in Western countries, and a leading cause of male cancer-related deaths. Although serum prostate-specific antigen (sPSA) is widely used for diagnostics, prognostics, and therapeutic monitoring purposes, its limitations are well known. The specificity of sPSA is poor and its use can lead to overdiagnosis and overtreatment. Tumor biopsies therefore remain the gold standard for cancer diagnosis. However, taking biopsies from the primary tumor is an invasive procedure with complications such as bleeding, urinary retention, infection and sepsis. Furthermore, PCa predominantly metastasizes to the bones and bone biopsies are hard to perform and often limited by the low yield of tumor tissue. For metastasized PCa that progressed under androgen deprivation therapy (ADT), termed metastatic castration-resistant PCa (mCRPC), many treatment options are available nowadays, including next generation androgen receptor targeting agents (ARTAs) (e.g. abiraterone and enzalutamide), taxane-based chemotherapy (docetaxel and cabazitaxel) and other agents such as radium-223 and sipuleucel-T [1–8]. De novo resistance to the ARTAs is observed in almost a quarter of the mCRPC patients. Moreover, cross-resistance is common for these drugs. However, and unfortunately, sPSA is not an adequate marker for evaluation of treatment response and biomarkers predicting treatment resistance are needed.
Reversibility of castration resistance status after Radium-223 dichloride treatment: clinical evidence and review of the literature
Published in International Journal of Radiation Biology, 2019
Maria Ricci, Viviana Frantellizzi, Nadia Bulzonetti, Giuseppe De Vincentis
CRPC refers to the continuous progression of PCa following ADT. In recent years, the definition of castration resistance has changed substantially. Currently, only symptom progression is not sufficient to diagnose CRPC. According to the Advanced PCa Consensus Conference the diagnosis of CRPC should include both a serum testosterone level of the castrated <1.7 nmol/l or <50 ng/dL and biochemical progression. Biochemical progression is defined as an increase of PSA expression levels, twice in a row from an interval of 1 week or >3 consecutive measurements with the lowest value increased >50% and >2 g/l, and ≥2 increase in novel lesions based on bone scanning or soft tissue lesions with the corresponding evaluation criteria of the solid tumor (Thomas et al. 2016; Huang et al. 2018). Treatment options at this stage of the disease include taxane-based chemotherapy, dendritic cell vaccination-based immunotherapy, the calcium mimic Radium-223 dichloride targeting bone metastases, and second-generation AR-targeting therapies (Scher et al. 2012; Fizazi et al. 2012; Baldari et al. 2017; Frantellizzi et al. 2018). However, resistance to therapy invariably occurs at these advanced stages of the disease, including ab initio resistance and/or cross-resistance to previously used drugs (Tran et al. 2009; Beer et al. 2014).
Related Knowledge Centers
- Aminoglycoside
- Antimicrobial Resistance
- Efflux
- Nalidixic Acid
- Topoisomerase
- Ciprofloxacin
- Quinolone Antibiotic
- Phage Therapy
- Evolutionary Therapy
- Multiple Drug Resistance