Antitumor alkylating agents: in vitro cross-resistance and collateral sensitivity studies

1993 ◽  
Vol 33 (2) ◽  
pp. 113-122 ◽  
Author(s):  
Emil Frei ◽  
Sylvia A. Holden ◽  
Rene Gonin ◽  
David J. Waxman ◽  
Beverly A. Teicher
Keyword(s):  
Alkylating Agents ◽  
Cross Resistance ◽  
Collateral Sensitivity ◽  
Sensitivity Studies ◽  
Antitumor Alkylating Agents

scholarly journals Antibiotic collateral sensitivity is contingent on the repeatability of evolution

2017 ◽  
Author(s):  
Daniel Nichol ◽  
Joseph Rutter ◽  
Christopher Bryant ◽  
Andrea M Hujer ◽  
Sai Lek ◽  
...  
Keyword(s):  
Experimental Evolution ◽  
Treatment Strategies ◽  
Therapeutic Benefit ◽  
Cross Resistance ◽  
Health Crisis ◽  
Collateral Sensitivity ◽  
Drug Regimens ◽  
Novel Treatment Strategies ◽  
Increased Susceptibility

AbstractAntibiotic resistance represents a growing health crisis that necessitates the immediate discovery of novel treatment strategies. One such strategy is the identification of collateral sensitivities, wherein evolution under a first drug induces susceptibility to a second. Here, we report that sequential drug regimens derived from in vitro evolution experiments may have overstated therapeutic benefit, predicting a collaterally sensitive response where cross resistance ultimately occurs. We quantify the likelihood of this phenomenon by use of a mathematical model parametrised with combinatorially complete fitness landscapes for Escherichia coli. Through experimental evolution we then verify that a second drug can indeed stochastically exhibit either increased susceptibility or increased resistance when following a first. Genetic divergence is confirmed as the driver of this differential response through targeted and whole genome sequencing. Taken together, these results highlight that the success of evolutionarily-informed therapies is predicated on a rigorous probabilistic understanding of the contingencies that arise during the evolution of drug resistance.

A Comparison of the Lethal and Kinetic Effects of Doxorubicin and 4′-EPI-Doxorubicin in Vitro

1982 ◽  
Vol 68 (1) ◽  
pp. 29-37 ◽  
Author(s):  
Bridget T. Hill ◽  
Richard D.H. Whelan
Keyword(s):  
Cell Lines ◽  
Cross Resistance ◽  
Drug Resistant ◽  
Human Cell Lines ◽  
Lethal Effects ◽  
Collateral Sensitivity ◽  
L5178y Cell ◽  
Kinetic Effects ◽  
Resistant Cells

« In vitro » lethal and kinetic effects of 4′-epi-doxorubicin (EPI-DXR) have been established and compared with those of doxorubicin (14-hydroxy-daunorubicin, adriamycin, NSC-123127, DXR). Both drugs show comparable cytotoxicity against a range of murine and human cell lines. Cytotoxicity increases exponentially with drug concentration and with duration of exposure. EPI-DXR like DXR exerts maximal lethal effects during the late S and G2 phases of the cycle in synchronised N1L8 Syrian hamster cells. Flow microfluorimetric data and measurements of mitotic indices provide evidence of population arrest in G2 with both drugs. Responses of various drug-resistant L5178Y cell lines were similar for DXR and EPI-DXR: (i) DXR-resistant cells exhibit complete cross-resistance to EPI-DXR, (ii) vincristine-resistant cells are cross-resistant to DXR and EPI-DXR, and (iii) methotrexate-resistant and 5-fluorouracil-resistant cells show collateral sensitivity to both drugs. These studies emphasise the similarities of DXR and EPI-DXR.

scholarly journals Resistance to the Cyclotide Cycloviolacin O2 in Salmonella enterica Caused by Different Mutations That Often Confer Cross-Resistance or Collateral Sensitivity to Other Antimicrobial Peptides

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Sohaib Z. Malik ◽  
Marius Linkevicius ◽  
Ulf Göransson ◽  
Dan I. Andersson
Keyword(s):  
Antimicrobial Peptides ◽  
Salmonella Enterica ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Fitness Costs ◽  
Content Type ◽  
Collateral Sensitivity ◽  
Fitness Advantage ◽  
Essential Components

ABSTRACT Antimicrobial peptides (AMPs) are essential components of innate immunity in all living organisms, and these potent broad-spectrum antimicrobials have inspired several antibacterial development programs in the past 2 decades. In this study, the development of resistance to the Gram-negative bacterium-specific peptide cycloviolacin O2 (cyO2), a member of the cyclotide family of plant miniproteins, was characterized in Salmonella enterica serovar Typhimurium LT2. Mutants isolated from serial passaging experiments in increasing concentrations of cyO2 were characterized by whole-genome sequencing. The identified mutations were genetically reconstituted in a wild-type background. The additive effect of mutations was studied in double mutants. Fitness costs, levels of resistance, and cross-resistance to another cyclotide, other peptide and nonpeptide antibiotics, and AMPs were determined. A variety of resistance mutations were identified. Some of these reduced fitness and others had no effect on fitness in vitro, in the absence of cyO2. In mouse competition experiments, four of the cyO2-resistant mutants showed a significant fitness advantage, whereas the effects of the mutations in the others appeared to be neutral. The level of resistance was increased by combining several individual resistance mutations. Several cases of cross-resistance and collateral sensitivity between cyclotides, other AMPs, and antibiotics were identified. These results show that resistance to cyclotides can evolve via several different types of mutations with only minor fitness costs and that these mutations often affect resistance to other AMPs.

Cross-resistance patterns in ACNU-resistant glioma sublines in culture

1991 ◽  
Vol 75 (2) ◽  
pp. 277-283 ◽  
Author(s):  
Yuji Saito ◽  
Yosihiro Nakada ◽  
Takuhiro Hotta ◽  
Takasi Mikami ◽  
Kaoru Kurisu ◽  
...  
Keyword(s):  
Alkylating Agents ◽  
Multidrug Resistant ◽  
Cellular Level ◽  
Cross Resistance ◽  
Mutagenic Action ◽  
Content Type ◽  
Rat Glioma ◽  
Resistance Patterns ◽  
Resistant Cells

✓ Three ACNU-resistant clones (R1, R3, and R12) were isolated from 9L rat glioma cells under selection pressure of ACNU in vitro. The authors have investigated the mechanisms of resistance and characteristics of these clones at the cellular level by studying cross-resistance patterns to chemical and physical agents. Although these resistant sublines showed complete cross-resistance to methyl-chloroethylnitrosourea (MCNU), no cross-resistance was observed for other alkylating agents, while each of the resistant sublines showed partial cross-resistance to structurally dissimilar toxic agents (vinblastine, Adriamycin, and VP-16). No difference in ACNU uptake was observed between 9L and R3 cells, and resistance patterns among alkylating agents suggested that the mechanism of ACNU resistance was specific to bifunctional nitrosoureas. Based on a transport study, this multidrug resistance could be explained by reduced intracellular uptake of these drugs, but there seemed little possibility that membrane P-glycoprotein, which usually is observed in typical multidrug-resistant cells, was expressed in these ACNU-resistant cells because enhanced drug efflux was not found in ACNU-resistant sublines. Significant collateral sensitivity to L-asparaginase indicated that ACNU might disturb the asparagine synthetic pathways by its mutagenic action. The increased level of total glutathione in the resistant sublines may be one mechanism of radiation or ACNU resistance.

scholarly journals 1592U89, a novel carbocyclic nucleoside analog with potent, selective anti-human immunodeficiency virus activity.

1997 ◽  
Vol 41 (5) ◽  
pp. 1082-1093 ◽  
Author(s):  
S M Daluge ◽  
S S Good ◽  
M B Faletto ◽  
W H Miller ◽  
M H St Clair ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Oral Bioavailability ◽  
Human Peripheral Blood ◽  
Cross Resistance ◽  
Immunodeficiency Virus ◽  
Carbocyclic Nucleoside ◽  
Hiv 1 ◽  
In Cells

1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with a unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of a wide variety of analogs containing a cyclopentene substitution for the 2'-deoxyriboside of natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. 1592U89 was equivalent in potency to 3'-azido-3'-deoxythymidine (AZT) in human peripheral blood lymphocyte (PBL) cultures against clinical isolates of HIV type 1 (HIV-1) from antiretroviral drug-naive patients (average 50% inhibitory concentration [IC50], 0.26 microM for 1592U89 and 0.23 microM for AZT). 1592U89 showed minimal cross-resistance (approximately twofold) with AZT and other approved HIV reverse transcriptase (RT) inhibitors. 1592U89 was synergistic in combination with AZT, the nonnucleoside RT inhibitor nevirapine, and the protease inhibitor 141W94 in MT4 cells against HIV-1 (IIIB). 1592U89 was anabolized intracellularly to its 5'-monophosphate in CD4+ CEM cells and in PBLs, but the di- and triphosphates of 1592U89 were not detected. The only triphosphate found in cells incubated with 1592U89 was that of the guanine analog (-)-carbovir (CBV). However, the in vivo pharmacokinetic, distribution, and toxicological profiles of 1592U89 were distinct from and improved over those of CBV, probably because CBV itself was not appreciably formed from 1592U89 in cells or animals (<2%). The 5'-triphosphate of CBV was a potent, selective inhibitor of HIV-1 RT, with Ki values for DNA polymerases (alpha, beta, gamma, and epsilon which were 90-, 2,900-, 1,200-, and 1,900-fold greater, respectively, than for RT (Ki, 21 nM). 1592U89 was relatively nontoxic to human bone marrow progenitors erythroid burst-forming unit and granulocyte-macrophage CFU (IC50s, 110 microM) and human leukemic and liver tumor cell lines. 1592U89 had excellent oral bioavailability (105% in the rat) and penetrated the CNS (rat brain and monkey cerebrospinal fluid) as well as AZT. Having demonstrated an excellent preclinical profile, 1592U89 has progressed to clinical evaluation in HIV-infected patients.

scholarly journals Combination of Niraparib, Cisplatin and Twist Knockdown in Cisplatin-Resistant Ovarian Cancer Cells Potentially Enhances Synthetic Lethality through ER-Stress Mediated Mitochondrial Apoptosis Pathway

2021 ◽  
Vol 22 (8) ◽  
pp. 3916
Author(s):  
Entaz Bahar ◽  
Ji-Ye Kim ◽  
Dong-Chul Kim ◽  
Hyun-Soo Kim ◽  
Hyonok Yoon
Keyword(s):  
Ovarian Cancer ◽  
Cell Culture ◽  
Cell Death ◽  
Er Stress ◽  
Cisplatin Resistance ◽  
Cross Resistance ◽  
Ovarian Cancer Cells ◽  
Apoptosis Pathway ◽  
Platinum Based Chemotherapy

Poly (ADP-ribose) polymerase 1 inhibitors (PARPi) are used to treat recurrent ovarian cancer (OC) patients due to greater survival benefits and minimal side effects, especially in those patients with complete or partial response to platinum-based chemotherapy. However, acquired resistance of platinum-based chemotherapy leads to the limited efficacy of PARPi monotherapy in most patients. Twist is recognized as a possible oncogene and contributes to acquired cisplatin resistance in OC cells. In this study, we show how Twist knockdown cisplatin-resistant (CisR) OC cells blocked DNA damage response (DDR) to sensitize these cells to a concurrent treatment of cisplatin as a platinum-based chemotherapy agent and niraparib as a PARPi on in vitro two-dimensional (2D) and three-dimensional (3D) cell culture. To investigate the lethality of PARPi and cisplatin on Twist knockdown CisR OC cells, two CisR cell lines (OV90 and SKOV3) were established using step-wise dose escalation method. In addition, in vitro 3D spheroidal cell model was generated using modified hanging drop and hydrogel scaffolds techniques on poly-2-hydroxylethly methacrylate (poly-HEMA) coated plates. Twist expression was strongly correlated with the expression of DDR proteins, PARP1 and XRCC1 and overexpression of both proteins was associated with cisplatin resistance in OC cells. Moreover, combination of cisplatin (Cis) and niraparib (Nira) produced lethality on Twist-knockdown CisR OC cells, according to combination index (CI). We found that Cis alone, Nira alone, or a combination of Cis+Nira therapy increased cell death by suppressing DDR proteins in 2D monolayer cell culture. Notably, the combination of Nira and Cis was considerably effective against 3D-cultures of Twist knockdown CisR OC cells in which Endoplasmic reticulum (ER) stress is upregulated, leading to initiation of mitochondrial-mediated cell death. In addition, immunohistochemically, Cis alone, Nira alone or Cis+Nira showed lower ki-67 (cell proliferative marker) expression and higher cleaved caspase-3 (apoptotic marker) immuno-reactivity. Hence, lethality of PARPi with the combination of Cis on Twist knockdown CisR OC cells may provide an effective way to expand the therapeutic potential to overcome platinum-based chemotherapy resistance and PARPi cross resistance in OC.

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