The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy

Anthracycline-based chemotherapy can result in the development of a cumulative and progressively developing cardiomyopathy. Doxorubicin is one of the most highly prescribed anthracyclines in the United States due to its broad spectrum of therapeutic efficacy. Interference with different mitochondrial processes is chief among the molecular and cellular determinants of doxorubicin cardiotoxicity, contributing to the development of cardiomyopathy. The present review provides the basis for the involvement of mitochondrial toxicity in the different functional hallmarks of anthracycline toxicity. Our objective is to understand the molecular determinants of a progressive deterioration of functional integrity of mitochondria that establishes a historic record of past drug treatments (mitochondrial memory) and renders the cancer patient susceptible to subsequent regimens of drug therapy. We focus on the involvement of doxorubicin-induced mitochondrial oxidative stress, disruption of mitochondrial oxidative phosphorylation, and permeability transition, contributing to altered metabolic and redox circuits in cardiac cells, ultimately culminating in disturbances of autophagy/mitophagy fluxes and increased apoptosis. We also suggest some possible pharmacological and nonpharmacological interventions that can reduce mitochondrial damage. Understanding the key role of mitochondria in doxorubicin-induced cardiomyopathy is essential to reduce the barriers that so dramatically limit the clinical success of this essential anticancer chemotherapy.

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Intracellular concentrations of Na+, K+, and Cl− of a moderately halophilic bacterium

Canadian Journal of Microbiology ◽

10.1139/m73-191 ◽

1973 ◽

Vol 19 (10) ◽

pp. 1181-1186 ◽

Cited By ~ 19

Author(s):

Masamiki Masui ◽

Sumi Wada

Keyword(s):

Cell Envelope ◽

Halophilic Bacterium ◽

Defined Medium ◽

Moderately Halophilic ◽

Whole Cells ◽

Moderately Halophilic Bacterium ◽

Intracellular Concentrations ◽

Isolated Cell ◽

Very High

The intracellular concentrations of Na+, K+, and Cl− of an unidentified moderately halophilic bacterium were determined. When the cells were grown at a late linear growth phase in a chemically defined medium containing 1, 2, or 3 M NaCl and 5.5 mM K+, the intracellular Na+ concentration (0.90–1.15 M) was independent of the Na+ in the medium. The K+ and Cl− concentrations were roughly on the same levels, respectively (0.67–0.89 M K+; 0.70–0.98 M Cl−). The Na+ and K+ per gram protein of the whole cells were 3.85 mmol and 2.96 mmol, respectively. When the cell envelope was incubated in a 2 M NaCl solution containing 5.5 mM K+ and 0.1 mM Mg2+, the Na+ concentration in the cell envelope was very high (6.49 mmol per gram protein) and K+ was concentrated up to about 41 times of the external K+ (0.36 mmol per gram protein). The high Na+ content of the isolated cell envelope may serve as one of the keys to elucidating a role of Na+ for the maintenance of the cell rigidity in this bacterium.

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Dual role of immunomodulation by anticancer chemotherapy

Nature Medicine ◽

10.1038/nm.3045 ◽

2013 ◽

Vol 19 (1) ◽

pp. 20-22 ◽

Cited By ~ 26

Author(s):

Michael R Shurin

Keyword(s):

Dual Role ◽

Anticancer Chemotherapy

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Role of adenosine monophosphate in regulation of metabolic pathways of perfused rat liver

Biochemical Journal ◽

10.1042/bj1110537 ◽

1969 ◽

Vol 111 (4) ◽

pp. 537-545 ◽

Cited By ~ 4

Author(s):

A. R. Hunter ◽

L. S. Jefferson

Keyword(s):

Amino Acids ◽

Metabolic Pathways ◽

Adenosine Monophosphate ◽

Supporting Evidence ◽

Pulse Labelling ◽

Perfusion Medium ◽

Intracellular Concentrations ◽

Glucose Output

1. By perfusion of rat livers with 3mm-AMP in the perfusion medium we obtain increased intracellular concentrations of AMP. 2. These high intracellular concentrations of AMP lead to an increased output of glucose and urea into the perfusion medium. 3. The increased output of glucose in livers from fed rats is brought about primarily by an AMP-stimulated breakdown of liver glycogen. In livers from starved rats the increase in glucose output is not as great, reflecting the low contents of glycogen in livers from starved rats. 4. AMP inhibits gluconeogenesis from lactate in perfused livers. In the presence of high concentrations of lactate, however, the counteracting effects of AMP to increase glycogenolysis and to inhibit gluconeogenesis result in little change in the net glucose output. 5. The increased urea output is brought about by increased breakdown of amino acids that are present in the perfusion medium. In livers from starved rats the overall urea production is much higher, indicating increased catabolism of amino acids and other nitrogenous substrates in the absence of carbohydrate substrates. 6. AMP causes an inhibition of incorporation of labelled precursors into protein and nucleic acid. This may result from increased catabolism of precursors of proteins and nucleic acids as reflected by the more rapid breakdown of nitrogenous compounds. In support of this hypothesis, cell-free systems for amino acid incorporation isolated from livers perfused with and without AMP are equally capable of supporting protein synthesis. 7. The labelling pattern of RNA in perfused livers corresponds very closely to those found by pulse-labelling in vivo. AMP in no way alters the qualitative nature of the labelling patterns. 8. We consider these results as supporting evidence for the role of the concentration ratio of AMP to ATP in controlling the metabolic pathways that lead to the formation of ATP.

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The role of Fas and FasL as mediators of anticancer chemotherapy

Drug Resistance Updates ◽

10.1054/drup.2001.0210 ◽

2001 ◽

Vol 4 (4) ◽

pp. 233-242 ◽

Cited By ~ 52

Author(s):

Vassiliki Poulaki ◽

Constantine S. Mitsiades ◽

Nicholas Mitsiades

Keyword(s):

Anticancer Chemotherapy

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Role of Pharmacogenetics in Adverse Drug Reactions: An Update towards Personalized Medicine

Frontiers in Pharmacology ◽

10.3389/fphar.2021.651720 ◽

2021 ◽

Vol 12 ◽

Author(s):

Emanuele Micaglio ◽

Emanuela T. Locati ◽

Michelle M. Monasky ◽

Federico Romani ◽

Francesca Heilbron ◽

...

Keyword(s):

Personalized Medicine ◽

Adverse Drug Reactions ◽

Stress Test ◽

Stevens Johnson Syndrome ◽

Drug Reactions ◽

Anticancer Chemotherapy ◽

Johnson Syndrome ◽

New Diagnosis ◽

Glucose 6 Phosphate Dehydrogenase

Adverse drug reactions (ADRs) are an important and frequent cause of morbidity and mortality. ADR can be related to a variety of drugs, including anticonvulsants, anaesthetics, antibiotics, antiretroviral, anticancer, and antiarrhythmics, and can involve every organ or apparatus. The causes of ADRs are still poorly understood due to their clinical heterogeneity and complexity. In this scenario, genetic predisposition toward ADRs is an emerging issue, not only in anticancer chemotherapy, but also in many other fields of medicine, including hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency, aplastic anemia, porphyria, malignant hyperthermia, epidermal tissue necrosis (Lyell’s Syndrome and Stevens-Johnson Syndrome), epilepsy, thyroid diseases, diabetes, Long QT and Brugada Syndromes. The role of genetic mutations in the ADRs pathogenesis has been shown either for dose-dependent or for dose-independent reactions. In this review, we present an update of the genetic background of ADRs, with phenotypic manifestations involving blood, muscles, heart, thyroid, liver, and skin disorders. This review aims to illustrate the growing usefulness of genetics both to prevent ADRs and to optimize the safe therapeutic use of many common drugs. In this prospective, ADRs could become an untoward “stress test,” leading to new diagnosis of genetic-determined diseases. Thus, the wider use of pharmacogenetic testing in the work-up of ADRs will lead to new clinical diagnosis of previously unsuspected diseases and to improved safety and efficacy of therapies. Improving the genotype-phenotype correlation through new lab techniques and implementation of artificial intelligence in the future may lead to personalized medicine, able to predict ADR and consequently to choose the appropriate compound and dosage for each patient.

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CoFactor: Folate Requirement for Optimization of 5-Fluouracil Activity in Anticancer Chemotherapy

Journal of Oncology ◽

10.1155/2010/934359 ◽

2010 ◽

Vol 2010 ◽

pp. 1-5 ◽

Cited By ~ 2

Author(s):

Muhammad Wasif Saif ◽

Nektaria Makrilia ◽

Kostas Syrigos

Keyword(s):

Clinical Trials ◽

Dna Synthesis ◽

Cytotoxic Activity ◽

Thymidylate Synthase ◽

Calcium Salt ◽

Anticancer Chemotherapy ◽

Important Target ◽

Anti Tumor Activity

Intracellular reduced folate exists as a “pool” of more than 6 interconvertable forms. One of these forms, 5,10 methylenetetrahydrofolic acid (CH2THF), is the key one-carbon donor and reduced folate substrate for thymidylate synthase (TS). This pathway has been an important target for chemotherapy as it provides one of the necessary nucleotide substrates for DNA synthesis. The fluoropyrimidine 5-fluorouracil (5-FU) exerts its main cytotoxic activity through TS inhibition. Leucovorin (5-formyltetrahydrofolate; LV) has been used to increase the intracellular reduced folate pools and enhance TS inhibition. However, it must be metabolized within the cell through multiple intracellular enzymatic steps to form CH2THF. CoFactor (USAN fotrexorin calcium, (dl)-5,10,-methylenepteroyl-monoglutamate calcium salt) is a reduced folate that potentiates 5-FU cytotoxicity. According to early clinical trials, when 5-FU is modulated by CoFactor instead of LV, there is greater anti-tumor activity and less toxicity. This review presents the emerging role of CoFactor in colorectal and nongastrointestinal malignancies.

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Evaluation of role of granulocyte macrophage colony stimulating factor (GM-CSF) in treatment of patients with perforation peritonitis: a prospective study

International Surgery Journal ◽

10.18203/2349-2902.isj20181607 ◽

2018 ◽

Vol 5 (5) ◽

pp. 1902

Author(s):

Tapan Singh Chauhan ◽

Chisel Bhatia ◽

Satish Dalal ◽

Nityasha Nara ◽

Tulit Chhabra

Keyword(s):

Antibiotic Therapy ◽

Hospital Stay ◽

Neutropenic Patient ◽

Septic Complications ◽

Systemic Complications ◽

Anticancer Chemotherapy ◽

Gm Csf ◽

Group A ◽

Group B

Background: GM-CSF has been demonstrated to be effective in reducing the incidence of infection in patients who receive myelosuppressive anticancer chemotherapy or patients who are neutropenic and agranulocytic. We study the role of GM-CSF in non-neutropenic patients with Systemic Inflammatory Response Syndrome (SIRS), infections and sepsis with impaired neutrophil function to access the current rationale for administering GM-CSF in addition to standard antibiotic therapy to critically ill patientsMethods: All patients undergoing surgery for peritonitis due to gastrointestinal perforations were included in this study and were divided into two groups alternatively to avoid any bias i.e. Group A 1, 3, 5 etc. and Group B 2, 4, 6 etc. Group A - all patients received GM-CSF along with standard antibiotics. Group B patients received antibiotics only. Course of patient in immediate postoperative period, time to improvement, duration of hospital stay, antibiotic therapy, rate of complications were compared.Results: Patients in group A had a lower duration of antibiotic therapy and hospital stay. Patients in group A took less time to show clinical improvement compared to patients in Group B. Group A also had a much lower rate of infectious and systemic complications compared to group B. Conclusions: Results of the present study show that GM-CSF is an important molecule when used as adjunct to antibiotics in cases of abdominal sepsis. Use of this growth factor is associated with less incidence of septic complications and morbidity, a shorter duration of antibiotic therapy and hospital stay without significantly compromising the cost. The results of present study help in identifying its role in non-neutropenic patient groups who are most likely to benefit from its administration.

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