The mechanism of action of radiosensitization of conventional chemotherapeutic agents*

https://doi.org/10.1053/srao.2003.50002Get rights and content

Abstract

It is not an exaggeration to state that most of the advances in curing cancer in the last decade have come from successful combinations of conventional chemotherapeutic agents with radiation therapy. Further improvements in therapy will depend on understanding the mechanisms by which chemotherapy improves the effectiveness of radiation in model systems and in patients. In this review, we discuss the mechanisms of action of the fluoropyrimidines, gemcitabine, and the platinums. The fluoropyrimidines (5-fluorouracil and fluorodeoxyuridine) increase the effectiveness of radiation chiefly when given before and during radiation. Increased radiation sensitivity occurs in cells that progress inappropriately into S phase in the presence of drug, suggesting a key role for dysregulation of S-phase checkpoints. Gemcitabine may radiosensitize by a similar mechanism, although the relative roles of specific DNA repair pathways (such as homologous end rejoining) and of apoptosis remain to be determined. For both of these categories of drugs, sensitization probably results when cells that are progressing inappropriately through S phase misrepair DNA damage inflicted by radiation. Thus, loss of the S-phase checkpoint in cancer cells may provide the molecular basis for selective killing of tumors compared with normal tissues. Cisplatin has multiple effects on cells, such as adduct formation and DNA damage repair inhibition, but the mechanism for selectivity against cancer cells compared with normal cells is not yet determined. The identification of the enzymatic targets for these drugs offers the potential to develop predictive assays for response and to develop methods of imaging the progress of therapy. Copyright 2003, Elsevier Science (USA). All rights reserved.

Section snippets

5-fluorouracil and fluorodeoxyuridine

5-fluorouracil (5FU) has been used extensively with radiation (for other reviews see1, 2). 5FU has both DNA-directed (through the inhibition of thymidylate synthase) and RNA-directed (through incorporation into the 3 species of RNA) effects. Although the disruption of either RNA or DNA synthesis can produce cytotoxicity, a substantial body of evidence suggests that radiosensitization is a result of inhibition of thymidylate synthase (summarized in1).

There are a number of mechanisms by which 5FU

Gemcitabine

The activity of gemcitabine against a variety of solid tumors combined with evidence that it affected deoxynucleotide triphosphate (dNTP) pools suggested that it might be a radiosensitizer. Initial studies showed significant enhancement of radiation-induced cell killing at both noncytotoxic and cytotoxic concentrations.16 There was no evidence of radiosensitization when the cells were irradiated before gemcitabine exposure, whereas the greatest enhancement ratio was observed when cells were

Platinum analogs

Platinum analogs, and specifically cis-diammino-platinum (II) (cisplatin), cis-diammine-1, 1-cyclobutane dicarboxylatoplatinum(II) (carboplatin), and more recently cis-[(1R,2R)-1,2-cyclohexanediamine-N,N'] [oxalato(2-)-O,O'] platinum (oxaliplatin), are being used clinically in combination with radiation in the treatment of a variety of solid tumors. It is not surprising that the mechanism of the interaction continues to be intensely investigated and is the focus of a number of reports.36, 37, 38

The need for better laboratory-clinical interactions

A fundamental issue in the application of conventional chemotherapeutic agents with radiation concerns determination of the molecular mechanism for the therapeutic index. In the case of the fluoropyrimidines and, perhaps, gemcitabine, it seems likely that dysfunctional S-phase checkpoints in cancer cells may permit inappropriate S phase progression, whereas normal cells arrest at the G1/S boundary and are relatively protected. The selectivity of the platinums radiosensitization remains a

References (74)

  • AC Begg et al.

    Radiosensitization in vitro by cisdiammine (1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin, JM8) and ethyl-enediammine-malonatoplatinum (II) (JM40)

    Radiother Oncol

    (1987)
  • P Carde et al.

    Effect of cis-dichlorodiammine platinum II and Xrays on mammalian cell survival

    Int J Radiat Oncol Biol Phys

    (1981)
  • LX Yang et al.

    Irradiation enhances cellular uptake of carboplatin

    Int J Radiat Oncol Biol Phys

    (1995)
  • GP Amorino et al.

    Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition

    Int J Radiat Oncol Biol Phys

    (1999)
  • T Servidei et al.

    The novel trinuclear platinum complex BBR3464 induces a cellular response different from cisplatin

    Eur J Can

    (2001)
  • PG Rose

    Chemoradiotherapy for cervical cancer

    Eur J Cancer

    (2002)
  • J Jassem

    Combined chemotherapy and radiation in locally advanced non-small cell lung cancer

    Lancet Oncol

    (2001)
  • O Rixe et al.

    Oxaliplatin, tetraplatin, cisplatin, and carboplatin: spectrum of activity in drug-resistant cell lines and in the cell lines of the National Cancer Institute's Anticancer Drug Screen panel

    Biochem Pharmacol

    (1996)
  • E Raymond et al.

    Oxaliplatin: A review of preclinical and clinical studies

    Ann Oncol

    (1998)
  • G Mathe et al.

    Antitumor activity of I-OHP in mice

    Cancer Lett

    (1985)
  • T Tashiro et al.

    Antitumor activity of a new platinum complex, oxalato (trans-1-1,2-diaminocyclohexane) platinum (II): New experimental data

    Biomed Pharmacother

    (1989)
  • G Mathe et al.

    Oxalato-platinum or I-OHP, a third-generation platinum complex: An experimental and clinical appraisal and preliminary comparison with cisplatinum and carboplatinum

    Biomed Pharmacother

    (1989)
  • A Cividalli et al.

    Radiosensitization by oxaliplatin in a mouse adenocarcinoma: Influence of treatment schedule

    Int J Radial Oncol Biol Phys

    (2002)
  • JE Byfield

    Useful interactions between 5-fluorouracil and radiation in man: 5-fluorouracil as a radiosensitizer

  • TS Lawrence et al.

    Fluoropyrimidine-mediated radiosensitization depends on cyclin E-dependent kinase activation

    Can Res

    (1996)
  • TS Lawrence et al.

    Fluorodeoxyuridine-mediated cytotoxicity and radiosensitization require S Phase progression

    Int J Radiat Biol

    (1996)
  • SN Boyer et al.

    E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway

    Can Res

    (1996)
  • DE Wazer et al.

    Immortalization of distinct human mammary epithelial cell types by human papilloma virus 16 E6 or E7

    Proc Natl Acad Sci U S A

    (1995)
  • R Zellars et al.

    The effect of p53 overexpression on radiation sensitivity of human colon cancer cells

    Rad Onc Invest

    (1997)
  • TA Rich

    Infusional chemoradiation for rectal and anal cancers

    Oncology (Huntington)

    (1999)
  • R Whittington et al.

    Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: A phase I Eastern Cooperative Oncology Group Trial

    J Clin Oncol

    (1995)
  • N Sawada et al.

    X-ray irradiation induces thymidine phosphorylase and enhances the efficacy of capecitabine (Xeloda) in human cancer xenografts

    Clin Can Res

    (1999)
  • Y Shirota et al.

    ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy

    J Clin Oncol

    (2001)
  • D Salonga et al.

    Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase

    Clin Can Res

    (2000)
  • DS Shewach et al.

    Metabolism of 2',2'-difluoro-2'-deoxycytidine and radiation sensitization of human colon carcinoma cells

    Can Res

    (1994)
  • TS Lawrence et al.

    Delayed radiosensitization of human colon carcinoma cells after a brief exposure to 2', 2'-difluoro-2'-deoxycytidine (Gemcitabine)

    Clin Can Res

    (1997)
  • JL Abbruzzese et al.

    A phase I clinical, plasma, and cellular pharmacology study of gemcitabine

    J Clin Oncol

    (1991)
  • Cited by (0)

    *

    Address reprint requests to Theodore S. Lawrence, MD, PhD, University of Michigan, Department of Radiation Oncology, 1500 E Medical Center Drive, B2C502 UH, Ann Arbor, MI 48109-0010.

    View full text