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Cytotoxic Drugs in the Modern Era of Personalized Medicine: Are They Still of Value?

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 5826

Special Issue Editor

Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, PI, Italy
Interests: clinical pharmacokinetics; chemotherapeutic agents; therapeutic drug monitoring
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For several years, cytotoxic drugs have been the cornerstone in oncology and haematology. The new class of antineoplastic drugs entered into the therapeutic armamentarium did not weaken the role of cytotoxic agents in the management of tumours. Indeed, the combination regimens revitalized their use through improved effectiveness. Furthermore, an ameliorated knowledge of their mechanisms of action and molecular pathways they targeted paved the way to the development of new drugs. These efforts were driven by the need for overcoming cancer cell resistance, and to reduce the risk of severe, and sometimes life-threatening, toxicities associated with their use. The paradigmatic example of 5-fluorouracil well describes how the landscape of this class of drugs has been changed. Indeed, the different infusion regimens, the development of oral prodrugs and the combination of an oral prodrug plus an enzymatic inhibitor improved the drug efficacy. Furthermore, the better knowledge of molecular mechanisms has fueled the search for predictive biomarkers of efficacy and tolerability based on the individual’s genotype and/or phenotype of patients. The analysis of either a single marker or a panel of pharmacokinetic and/or pharmacodynamic markers may enable the stratification of patients according to their expected therapeutic benefit or the probability of adverse reactions. More recently, the dissection of molecular mechanisms targeted or modulated by cytotoxic drugs has enabled the evaluation of their use in combination with immune checkpoint inhibitors, which represent one of the newest approaches in cancer therapy. Although some of them represent the dawning of cancer chemotherapy, cytotoxic drugs are still the underpinning of several combination regimens in oncology and haematology.

Prof. Dr. Antonello Di Paolo
Guest Editor

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Keywords

  • cytotoxic drugs
  • oncology
  • hematology
  • pharmacokinetics
  • pharmacogenetics
  • epigenetics
  • combination therapies
  • efficacy
  • tolerability
  • predictive markers
  • cancer resistance

Published Papers (2 papers)

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24 pages, 3882 KiB  
Article
Effective Drug Concentration and Selectivity Depends on Fraction of Primitive Cells
by Jan Jakub Lica, Miłosz Wieczór, Grzegorz Jan Grabe, Mateusz Heldt, Marta Jancz, Majus Misiak, Katarzyna Gucwa, Wioletta Brankiewicz, Natalia Maciejewska, Anna Stupak, Maciej Bagiński, Krzysztof Rolka, Andrzej Hellmann and Andrzej Składanowski
Int. J. Mol. Sci. 2021, 22(9), 4931; https://doi.org/10.3390/ijms22094931 - 06 May 2021
Cited by 27 | Viewed by 3173
Abstract
Poor efficiency of chemotherapeutics in the eradication of Cancer Stem Cells (CSCs) has been driving the search for more active and specific compounds. In this work, we show how cell density-dependent stage culture profiles can be used in drug development workflows to achieve [...] Read more.
Poor efficiency of chemotherapeutics in the eradication of Cancer Stem Cells (CSCs) has been driving the search for more active and specific compounds. In this work, we show how cell density-dependent stage culture profiles can be used in drug development workflows to achieve more robust drug activity (IC50 and EC50) results. Using flow cytometry and light microscopy, we characterized the cytological stage profiles of the HL-60-, A-549-, and HEK-293-derived sublines with a focus on their primitive cell content. We then used a range of cytotoxic substances—C-123, bortezomib, idarubicin, C-1305, doxorubicin, DMSO, and ethanol—to highlight typical density-related issues accompanying drug activity determination. We also showed that drug EC50 and selectivity indices normalized to primitive cell content are more accurate activity measurements. We tested our approach by calculating the corrected selectivity index of a novel chemotherapeutic candidate, C-123. Overall, our study highlights the usefulness of accounting for primitive cell fractions in the assessment of drug efficiency. Full article
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5 pages, 793 KiB  
Case Report
Axitinib in Ponatinib-Resistant B-Cell Acute Lymphoblastic Leukemia Harboring a T315L Mutation
by Valentina Giudice, Andrea Ghelli Luserna di Rorà, Bianca Serio, Roberto Guariglia, Maria Benedetta Giannini, Anna Ferrari, Giorgia Simonetti, Carmine Selleri and Giovanni Martinelli
Int. J. Mol. Sci. 2020, 21(24), 9724; https://doi.org/10.3390/ijms21249724 - 20 Dec 2020
Cited by 4 | Viewed by 1894
Abstract
Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are [...] Read more.
Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are frequent because of acquired somatic mutations in the BCR-ABL1 kinase domain causing resistance to first, second and third generation TKIs. Axitinib has shown in vitro and ex vivo activity in blocking ABL1; however, clinical trials exploring its efficacy in ALL are missing. Here, we presented a 77-year-old male with a diagnosis of Ph positive ALL resistant to ponatinib and carrying a rare threonine to leucine (T315L) mutation on BCR-ABL1 gene. The patient was treated with axitinib at 5 mg/twice daily as salvage therapy showing an immediate although transient benefit with an overall survival of 9.3 months. Further dose-finding and randomized clinical trials are required to assess the real efficacy of axitinib for adult Ph positive ALL resistant to third generation TKIs. Full article
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