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Cited by 301Cancer therapeutics and mechanismsColorectal Cancer Treatments and StudiesCancer Treatment and Pharmacology

Basis for effective combination cancer chemotherapy with antimetabolites

Peters, G.J., van der Wilt, C.L., van Moorsel, C.J.A., Kroep, J.R., Bergman, A.M., Ackland, S.P.·2000·Pharmacology & Therapeutics
DOI 10.1016/s0163-7258(00)00086-3
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Abstract

Most current chemotherapy regimens for cancer consist of empirically designed combinations, based on efficacy and lack of overlapping toxicity. In the development of combinations, several aspects are often overlooked: (1) possible metabolic and biological interactions between drugs, (2) scheduling, and (3) different pharmacokinetic profiles. Antimetabolites are used widely in chemotherapy combinations for treatment of various leukemias and solid tumors. Ideally, the combination of two or more agents should be more effective than each agent separately (synergism), although additive and even antagonistic combinations may result in a higher therapeutic efficacy in the clinic. The median-drug effect analysis method is one of the most widely used methods for in vitro evaluation of combinations. Several examples of classical effective antimetabolite-(anti)metabolite combinations are discussed, such as that of methotrexate with 6-mercaptopurine or leucovorin in (childhood) leukemia and 5-fluorouracil (5FU) with leucovorin in colon cancer. More recent combinations include treatment of acute-myeloid leukemia with fludarabine and arabinosylcytosine. Other combinations, currently frequently used in the treatment of solid malignancies, include an antimetabolite with a DNA-damaging agent, such as gemcitabine with cisplatin and 5FU with the cisplatin analog oxaliplatin. The combination of 5FU and the topoisomerase inhibitor irinotecan is based on decreased repair of irinotecan-induced DNA damage. These combinations may increase induction of apoptosis. The latter combinations have dramatically changed the treatment of incurable cancers, such as lung and colon cancer, and have demonstrated that rationally designed drug combinations offer new possibilities to treat solid malignancies.

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  • Inducing DNA damage with genotoxic chemotherapies can sensitize cells to inhibitors of nucleotide biosynthesis.

    “Inducing DNA damage with the use of genotoxic chemotherapies can sensitize cells to inhibitors of nucleotide biosynthesis (Brown et al., 2017; Peters et al., 2000), suggesting that oncogenic mutations that reduce the DNA damage response is one explanation for why a therapeutic window exists for antimetabolite compounds.”

    From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Peters et al., 2000

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Authors
Peters, G. J., van der Wilt, C. L., van Moorsel, C. J. A., Kroep, J. R., Bergman, A. M., & Ackland, S. P.
Affiliations
Vrije Universiteit Amsterdam (NL)
Corresponding author
Peters, G.J.
ORCID
Venue
Pharmacology & Therapeutics
Publisher
Elsevier BV
Published
2000-08
Volume
87
Issue
2-3
Pages
227-253
ISSN
0163-7258 (ISSN-L)
DOI
10.1016/s0163-7258(00)00086-3
OpenAlex
W2068581230
Cited by
301
References
198
Citations by year
2026: 4 · 2025: 6 · 2024: 7 · 2023: 15 · 2022: 16 · 2021: 9 · 2020: 12 · 2019: 14 · 2018: 11 · 2017: 15 · 2016: 12 · 2015: 13 · 2014: 11 · 2013: 12 · 2012: 12
FWCI
0.37
Type
journal article
Language
en
Open access
closed
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
Keywords
combination chemotherapy, antimetabolites, drug interactions, drug scheduling, pharmacokinetics, synergistic effect, methotrexate, 6-mercaptopurine, leucovorin, 5-fluorouracil, fludarabine, cytarabine, acute myeloid leukemia, gemcitabine, cisplatin, oxaliplatin, irinotecan, topoisomerase inhibitors, DNA repair, apoptosis, leukemia, solid tumors
MeSH terms
Gemcitabine, Antimetabolites, Antineoplastic, Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Colonic Neoplasms, Deoxycytidine, Deoxycytidine Kinase, Drug Therapy, Fluorouracil, Humans, Leukemia, Neoplasms, Thymidylate Synthase

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