Biological basis for chemo-radiotherapy interactions

doi:10.1016/S0959-8049(01)00360-4

European Journal of Cancer

Volume 38, Issue 2, 2002, Pages 223-230

https://doi.org/10.1016/S0959-8049(01)00360-4 Get rights and content

Abstract

For over 10 years, chemo-radiotherapeutic combinations have been used to treat locally advanced epithelial tumours. The rationale for these combinations relies on spatial cooperation or interaction between modalities. Interactions may take place (i) at the molecular level, with altered DNA repair or modification of the lesions induced by drugs or radiation, (ii) at the cellular level, notably through cytokinetic cooperation arising from differential sensitivity of the various compartments of the cell cycle to the drug or radiation, and (iii) at the tissue level, including reoxygenation, increased drug uptake or inhibition of repopulation or angiogenesis. Some mechanisms underlying interaction of radiation with cis-diammino-platinum (II) (cis-Pt), 5-fluoro-2′-deoxyuridine (5-FU), taxanes and gemcitabine are described. It is shown how various mechanisms including cell synchronisation and reoxygenation concur to paclitaxel-induced radiosensitisation. In the future, specific targeting of tumours, for example, with the epidermal growth factor receptor (EGFR) or angiogenesis inhibitors, should be achieved in order to increase the therapeutic index.

Section snippets

Quantification of interactions between the drugs and radiations

If the cytotoxic response to the drug or radiation does not follow an exponential dose dependence, as is the case in most instances, the determination of the additivity status of the radiation–drug interaction cannot be reached directly from the inter-comparison of the survival curves. Moreover, data from combined treatment consist of three variables, namely the doses of the two agents and the resulting outcome. To overcome this problem, Steel and Peckham 1, 4 proposed a method based on the

Molecular mechanisms of interaction

Antitumour drugs may provide various mechanisms of interaction with radiation including DNA repair inhibition, cell-cycle redistribution, or altered cytokinesis or apoptosis. The relative importance of these mechanisms has seldom been evaluated, even for in vitro studies. For each mechanisms, we shall provide examples with current antitumour drugs.

Cytokinetic cooperation

It has long been known that radiosensitivity changes with the progression of cells through the cell cycle. The S phase is most radioresistant, and the G2-M phase is usually most radiosensitive 40, 41. For this reason, a large increase in radiation susceptibility is observed as proliferating cells are exposed in close temporal proximity with radiation, to drugs which specifically kill cells in S phase. This is the case for the camptothecin and camptothecin analogues acting as topoisomerase I

The search for tumour specificity

The way to a more efficient anticancer treatment would be to target tumours with treatments eliciting minimal response in surrounding, dose-limiting normal tissue. Radiotherapy takes advantage of differential sublethal damage repair in tumours versus normal tissue. Unfortunately, there is no convincing evidence to show that normal tissue sparing is retained when the chemo-radiotherapy combination is used, and, in fact, randomised trials for the appreciation of the late toxicity of

Conclusion

Concomitant chemo-radiotherapy turns out to be a widely accepted approach for the treatment of locally advanced epithelial carcinomas. Laboratory studies may contribute to drug development and help the physician in three different ways.

First, in selecting drugs which present a potential for radiosensitisation or for additive cytotoxicity. This requires measuring the strength of the effect, and determining whether the drugs are able or not to inhibit the repair of radiation-induced damage. It

Acknowledgments

The authors wish to thank Electricité de France (RB 2001-02) and the Association pour la Recherche sur le Cancer (ARC 9746) for financial support.

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Biological basis for chemo-radiotherapy interactions

Abstract

Section snippets

Quantification of interactions between the drugs and radiations

Molecular mechanisms of interaction

Cytokinetic cooperation

The search for tumour specificity

Conclusion

Acknowledgments

Int. J. Radiat. Oncol. Biol. Phys.

Radiother. Oncol.

Biochimie

Int. J. Radiat. Oncol. Biol. Phys.

Biochimica et Biophysica Acta

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Biophys. J.

Int. J. Radiat. Oncol. Biol. Phys.

Current Biol.

Gynecol. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Radiother. Oncol.

Int. J. Radiat. Oncol. Biol. Phys.

Exp. Cell. Res.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Radiother. Oncol.

J. Biol. Chem.

Int. J. Radiat. Oncol. Biol. Phys.

Int. J. Radiat. Oncol. Biol. Phys.

Effects of concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer

N. Engl. J. Med.

Exploitable mechanisms in combined radiotherapy-chemotherapythe concept of additivity

Int. J. Radiat. Oncol. Biol. Phys.

Repair and cell cycle interactions in radiation sensitization by the topoisomerase II poison etoposide

Cancer Res.

Poly(ADP-ribose) polymerase, a major determinant of early cell response to ionising radiation

Int. J. Radiat. Biol.

HMG-domain proteins specifically inhibit the repair of the major DNA adduct of the anticancer drug cisplatin by human excision nuclease

Proc. Natl. Acad. Sci. USA

The role of DNA mismatch repair in drug resistance

Clin. Cancer Res.

Production of DNA double-strand breaks by interactions between carboplatin and radiationa potential mechanism for radiopotentiation

Radiat. Res.

In situ localization of DNA topoisomerase II, a major polypeptide component of the Drosophila nuclear matrix fraction

Proc. Natl. Acad. Sci. USA

Localization of topoisomerase II in mitotic chromosomes

J. Cell. Biol.

Newly replicated DNA is associated with DNA topoisomerase II in cultured rat prostatic adenocarcinoma cells

Nature

Radiation-induced arrest of cells in G2 phase elicits hypersensitivity to DNA double-strand break inducers and an altered pattern of DNA cleavage upon re-irradiation

Int. J. Radiat. Biol.

Biphasic survival curves for XRS radiosensitive cellssubpopulations or transient expression of repair competence?

Int. J. Radiat. Biol.

Absence of p350 subunit of DNA-activated protein kinase from a radiosensitive human cell line

Science

Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin

Cancer Res.

Wortmannin is a potent inhibitor of DNA double strand break but not single strand break repair in Chinese hamster ovary cells

Carcinogenesis

Wortmannin inhibits repair of DNA double-strand breaks in irradiated normal human cells

Radiat. Res.

Fluorouracilbiochemistry and pharmacology

J. Clin. Oncol.

Radiosensitizing nucleosides

J. Natl. Cancer Inst.

Radiosensitization by fluorodeoxyuridineeffects of thymidylate synthase inhibition and cell synchronization

Cancer Res.

Action of 2′,2′-difluorodeoxycytidine on DNA synthesis

Cancer Res.

Preclinical studies of chemotherapy and radiation therapy for pancreatic carcinoma

Cancer

The effect of 2′,2′-difluorodeoxycytidine (dFdC, gemcitabine) on radiation-induced cell lethality in two human head and neck squamous carcinoma cell lines differing in intrinsic radiosensitivity

Int. J. Radiat. Biol.

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

Cancer Res.