scholarly journals Emerging Nano-Based Strategies Against Drug Resistance in Tumor Chemotherapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Lei Cao ◽  
Yuqin Zhu ◽  
Weiju Wang ◽  
Gaoxiong Wang ◽  
Shuaishuai Zhang ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Resistance Mechanisms ◽  
Patient Treatment ◽  
Tumor Resistance ◽  
New Horizons ◽  
Normal Tissues ◽  
Alternative Drug ◽  
Delivery Strategies ◽  
Tumor Types

Drug resistance is the most significant causes of cancer chemotherapy failure. Various mechanisms of drug resistance include tumor heterogeneity, tumor microenvironment, changes at cellular levels, genetic factors, and other mechanisms. In recent years, more attention has been paid to tumor resistance mechanisms and countermeasures. Nanomedicine is an emerging treatment platform, focusing on alternative drug delivery and improved therapeutic effectiveness while reducing side effects on normal tissues. Here, we reviewed the principal forms of drug resistance and the new possibilities that nanomaterials offer for overcoming these therapeutic barriers. Novel nanomaterials based on tumor types are an excellent modality to equalize drug resistance that enables gain more rational and flexible drug selectivity for individual patient treatment. With the emergence of advanced designs and alternative drug delivery strategies with different nanomaterials, overcome of multidrug resistance shows promising and opens new horizons for cancer therapy. This review discussed different mechanisms of drug resistance and recent advances in nanotechnology-based therapeutic strategies to improve the sensitivity and effectiveness of chemotherapeutic drugs, aiming to show the advantages of nanomaterials in overcoming of drug resistance for tumor chemotherapy, which could accelerate the development of personalized medicine.

scholarly journals Approaches to identifying drug resistance mechanisms to clinically relevant treatments in childhood rhabdomyosarcoma

2022 ◽  
Author(s):  
Samson Ghilu ◽  
Christopher L. Morton ◽  
Angelina V. Vaseva ◽  
Siyuan Zheng ◽  
Raushan T. Kurmasheva ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Risk ◽  
Tumor Regression ◽  
Population Level ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Tumor Resistance ◽  
Intrinsic Resistance ◽  
Clinical Resistance

Aim: Despite aggressive multiagent protocols, patients with metastatic rhabdomyosarcoma (RMS) have poor prognosis. In a recent high-risk trial (ARST0431), 25% of patients failed within the first year, while on therapy and 80% had tumor progression within 24 months. However, the mechanisms for tumor resistance are essentially unknown. Here we explore the use of preclinical models to develop resistance to complex chemotherapy regimens used in ARST0431. Methods: A Single Mouse Testing (SMT) protocol was used to evaluate the sensitivity of 34 RMS xenograft models to one cycle of vincristine, actinomycin D, cyclophosphamide (VAC) treatment. Tumor response was determined by caliper measurement, and tumor regression and event-free survival (EFS) were used as endpoints for evaluation. Treated tumors at regrowth were transplanted into recipient mice, and the treatment was repeated until tumors progressed during the treatment period (i.e., became resistant). At transplant, tumor tissue was stored for biochemical and omics analysis. Results: The sensitivity to VAC of 34 RMS models was determined. EFS varied from 3 weeks to > 20 weeks. Tumor models were classified as having intrinsic resistance, intermediate sensitivity, or high sensitivity to VAC therapy. Resistance to VAC was developed in multiple models after 2-5 cycles of therapy; however, there were examples where sensitivity remained unchanged after 3 cycles of treatment. Conclusion: The SMT approach allows for in vivo assessment of drug sensitivity and development of drug resistance in a large number of RMS models. As such, it provides a platform for assessing in vivo drug resistance mechanisms at a “population” level, simulating conditions in vivo that lead to clinical resistance. These VAC-resistant models represent “high-risk” tumors that mimic a preclinical phase 2 population and will be valuable for identifying novel agents active against VAC-resistant disease.

scholarly journals Bi-clustering based biological and clinical characterization of colorectal cancer in complementary to CMS classification

2018 ◽  
Author(s):  
Sha Cao ◽  
Wennan Chang ◽  
Changlin Wan ◽  
Yong Zhang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Large Scale ◽  
Molecular Subtype ◽  
Resistance Mechanisms ◽  
Low Rank ◽  
Data Sets ◽  
Alternative Drug ◽  
Transcriptomics Data ◽  
Consensus Molecular Subtype

In light of the marked differences in the intrinsic biological underpinnings and prognostic outcomes among different subtypes, Consensus Molecular Subtype (CMS) classification provides a new taxonomy of colorectal cancer (CRC) solely based on transcriptomics data and has been accepted as a standard rule for CRC stratification. Even though CMS was built on highly cancer relevant features, it suffers from limitations in capturing the promiscuous mechanisms in a clinical setting. There are at least two facts about using transcriptomic data for prognosis prediction: the engagement of genes or pathways that execute the clinical response pathway are highly dynamic and interactive with others; and a predefined patient stratification not only largely decrease the statistical analysis power, but also excludes the fact that clusters of patients that confer similar clinical outcomes may or may not overlap with a pre-defined subgrouping. To enable a flexible and prospective stratified exploration, we here present a novel computational framework based on bi-clustering aiming to identify gene regulatory mechanisms associated with various biological, clinical and drug-resistance features, with full recognition of the transiency of transcriptional regulation and complicacies of patients subgrouping with regards to different biological and clinical settings. Our analysis on multiple large scale CRC transcriptomics data sets using a bi-clustering based formulation suggests that the detected local low rank modules can not only generate new biological understanding coherent to CMS stratification, but also identify predictive markers for prognosis that are general to CRC or CMS dependent, as well as novel alternative drug resistance mechanisms. Our key results include: (1) a comprehensive annotation of the local low rank module landscape of CRC; (2) a mechanistic relationship between different clinical subtypes and outcomes, as well as their characteristic biological underpinnings, visible through a novel consensus map; and (3) a few (novel) resistance mechanisms of Oxaliplatin, 5-Fluorouracil, and the FOLFOX therapy are revealed, some of which are validated on independent datasets.

scholarly journals Bypassing the Blood–Brain Barrier: Direct Intracranial Drug Delivery in Epilepsies

Pharmaceutics ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1134
Author(s):  
Manuela Gernert ◽  
Malte Feja
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Adverse Effects ◽  
Blood Brain Barrier ◽  
Neurological Diseases ◽  
Invasive Procedure ◽  
Resistance Mechanisms ◽  
Brain Barrier ◽  
Blood Brain ◽  
Drug Concentrations

Epilepsies are common chronic neurological diseases characterized by recurrent unprovoked seizures of central origin. The mainstay of treatment involves symptomatic suppression of seizures with systemically applied antiseizure drugs (ASDs). Systemic pharmacotherapies for epilepsies are facing two main challenges. First, adverse effects from (often life-long) systemic drug treatment are common, and second, about one-third of patients with epilepsy have seizures refractory to systemic pharmacotherapy. Especially the drug resistance in epilepsies remains an unmet clinical need despite the recent introduction of new ASDs. Apart from other hypotheses, epilepsy-induced alterations of the blood–brain barrier (BBB) are thought to prevent ASDs from entering the brain parenchyma in necessary amounts, thereby being involved in causing drug-resistant epilepsy. Although an invasive procedure, bypassing the BBB by targeted intracranial drug delivery is an attractive approach to circumvent BBB-associated drug resistance mechanisms and to lower the risk of systemic and neurologic adverse effects. Additionally, it offers the possibility of reaching higher local drug concentrations in appropriate target regions while minimizing them in other brain or peripheral areas, as well as using otherwise toxic drugs not suitable for systemic administration. In our review, we give an overview of experimental and clinical studies conducted on direct intracranial drug delivery in epilepsies. We also discuss challenges associated with intracranial pharmacotherapy for epilepsies.

scholarly journals The Genomic Stability at the Coding Regions of the Multidrug Transporter Gene ABCB1: Insights into the Development of Alternative Drug Resistance Mechanisms in Human Leukemia Cells

2019 ◽  
Author(s):  
Kevin G. Chen ◽  
George E. Duran ◽  
Mark J. Mogul ◽  
Yan C. Wang ◽  
Kevin L. Ross ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mechanisms ◽  
Leukemia Cells ◽  
Multidrug Transporter ◽  
Drug Resistant ◽  
Transporter Gene ◽  
Cellular Models ◽  
Coding Regions ◽  
Alternative Drug ◽  
Selection Of

ABSTRACTDespite considerable efforts in reversing clinical multidrug resistance (MDR), targeting the predominant multidrug transporter ABCB1/P-glycoprotein (P-gp) based on small molecule inhibitors has been hindered. This may be due to the emergence of alternative drug resistance mechanisms. However, the non-specific P-gp inhibitor cyclosporine (CsA) showed significant clinical benefits in patients with acute myeloid leukemia (AML), which likely represents the only proof-of-principle clinical trial using several generations of MDR inhibitors. Nevertheless, the mechanisms that underlie this successful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models. In this study, we report the development of two erythroleukemia variants, RVC and RDC, which were derived by step-wise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations, respectively. Interestingly, both RVC and RDC, which retained P-gp expression, showed altered MDR phenotypes that were resistant to cyclosporine modulation. The ABCB1 coding regions were genetically stable even under long-term stringent drug selection. Genomically, ABCB1 is likely the most stable ABC transporter gene when comparing with several ABC superfamily members (such as ABCA1, ABCC1, CFTR, and ABCG2). Our findings suggested that non-P-gp mechanisms were likely responsible for the resistance to CsA modulation in both RVC and RDC cells. Moreover, we found that CsA played a role in undermining the selection of highly drug-resistant cells via induction of low level and unstable drug resistance, thus shedding some light on the benefits of CsA in treating certain types of AML patients.

scholarly journals Antifungal and Antiparasitic Drug Delivery

Pharmaceutics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 324
Author(s):  
Juan José Torrado ◽  
Dolores R. Serrano ◽  
Javier Capilla
Keyword(s):  
Drug Delivery ◽  
Drug Resistance ◽  
Water Solubility ◽  
Parasitic Diseases ◽  
Special Issue ◽  
High Concentration ◽  
Administration Routes ◽  
Antiparasitic Drug ◽  
Delivery Strategies ◽  
Antiparasitic Drugs

Fungal and parasitic diseases affect more than a billion people across the globe, one-sixth of the world’s population, mostly located in developing countries. The lack of effective and safer treatments combined with a deficient diagnosis lead to serious chronic illness or even death. There is a mismatch between the rate of drug resistance and the development of new medicines. Formulation of antifungal and antiparasitic drugs adapted to different administration routes is challenging, bearing in mind their poor water solubility, which limits their bioavailability and efficacy. Hence, there is an unmet clinical need to develop vaccines and novel formulations and drug delivery strategies that can improve the bioavailability and therapeutic effect by enhancing their dissolution, increasing their chemical potency, stabilising the drug and targeting high concentration of drug to the infection sites. This Editorial regards the ten research contributions presented in the Special Issue “Antifungal and Antiparasitic Drug Delivery”.

Innovative Drug Delivery Strategies for Topical Photodynamic Therapy using Porphyrin Precursors

2007 ◽  
Vol 26 (2) ◽  
pp. 105-116 ◽  
Author(s):  
Desmond I. J. Morrow ◽  
Martin J. Garland ◽  
Paul A. McCarron ◽  
A. David Woolfson ◽  
Ryan F. Donnelly
Keyword(s):  
Drug Delivery ◽  
Photodynamic Therapy ◽  
Innovative Drug ◽  
Delivery Strategies

HER2-Mediated Anticancer Drug Delivery: Strategies to Prepare Targeting Ligands Highly Specific for the Receptor

2015 ◽  
Vol 22 (21) ◽  
pp. 2525-2538 ◽  
Author(s):  
Enrica Calce ◽  
Luca Monfregola ◽  
Michele Saviano ◽  
Stefania De Luca
Keyword(s):  
Drug Delivery ◽  
Anticancer Drug ◽  
Anticancer Drug Delivery ◽  
Delivery Strategies

Targeting Nodal and Cripto-1: Perspectives Inside Dual Potential Theranostic Cancer Biomarkers

2019 ◽  
Vol 26 (11) ◽  
pp. 1994-2050 ◽  
Author(s):  
Annamaria Sandomenico ◽  
Menotti Ruvo
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Normal Development ◽  
Cancer Biomarkers ◽  
Normal Tissues ◽  
Tumor Relapse ◽  
Developmental Factors ◽  
Theranostic Agents ◽  
Tumor Types ◽  
Embryonic Signaling

Background:Elucidating the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of onco-fetal players which have physiological roles during normal development but result aberrantly re-activated in tumors. In this context, Nodal and Cripto-1 are recognized as onco-developmental factors, which are absent in normal tissues but are overexpressed in several solid tumors where they can serve as theranostic agents.Objective:To collect, review and discuss the most relevant papers related to the involvement of Nodal and Cripto-1 in the development, progression, recurrence and metastasis of several tumors where they are over-expressed, with a particular attention to their occurrence on the surface of the corresponding sub-populations of cancer stem cells (CSC).Results:We have gathered, rationalized and discussed the most interesting findings extracted from some 370 papers related to the involvement of Cripto-1 and Nodal in all tumor types where they have been detected. Data demonstrate the clear connection between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. We have also reviewed and highlighted the potential of targeting Nodal, Cripto-1 and the complexes that they form on the surface of tumor cells, especially of CSC, as an innovative approach to detect and suppress tumors with molecules that block one or more mechanisms that they regulate.Conclusion:Overall, Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic anti-tumor agents that target normal as well as CSC subpopulations and overcome both pharmacological resistance and tumor relapse.

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