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Biological Basis for Chemo-Radiotherapy Interactions

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Biological Basis for Chemo-Radiotherapy Interactions European Journal of Cancer 38 (2002) 223–230 www.ejconline.com Biological basis for chemo-radiotherapy interactions C. Hennequina,a,*, V. Favaudonbb aaService de Cance´ ´ rologie-Radiothe´ ´ rapie, Ho ˆ ˆ pital Saint-Louis, 1 avenue Claude Vellefeaux, 75010 Paris, France bbUnite´ ´ 350 INSERM, Institut Curie-Recherche, Labs. 110-112, Centre Universitaire, 91405 Orsay Cedex, France Received 29 June 2001; accepted 29 August 2001 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 ciscis-diammino-platinum (II) (ciscis-Pt), 5-fluoro-200 -deoxy- uridine (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. ## 2002 Published by Elsevier Science Ltd. Keywords: Chemo-radiotherapy; Taxane; Gemcitabine In In 1979, Steel and his coworkers proposed a theo-o- Where the drug carrieries protection againsinst radiatiatioionn retical frame for the prediction of the outcome of com- damage to normal healthy tissues, this would theoretically bined tretreatments with cytotoxic chemotherapy and allow the radiation dose to the tumour to be increased. In radiotherapy [1,2], including: general, however, to obtain spatial cooperation or addi- tivity, it is necessary to use chemo- and radiotherapy each .. Spatial cooperation. This concept was devised to at full doses or, at least, drugs at cytotoxic levels, yet there mean that chemotherapy and radiotiotherapy are may be a few exceptions. For example, one European primarily designed to target metastatic disease and Organiznizatiation for Research and Treatment of Cancerr the primitive tumour site, respectively. (EORTC) trial in lung cancer [3] where ciscisplatin was .. Additivity, where it is inintetendnded ththat boboth mod-d- used at a sub-cytotoxic concentration with conventional alalititieies ininteteraract in a pupurerely adaddidititive mode wiwithth radiotherapy, gave evidence of a substantial improvement regard to sterilisation of the target tumour. in local control of the tumour. On the other hand, supra- .. Infra-additivity (or protection), where the chemo- additive interaction usually relies on molecular interac- therapeutic agent inhibits tumour regression (or tion between the drug and radiation. Numerous mechan- protects normal tissue) by radiation. isms of interactions have already been described and will .. Supra-additivity, or enenhahancnced tutumour rerespspononsese,, b e be summarised below. This notwithstanding, in most where the ususe of cocombininatatioions enends in a morere instances the benefit of chemo-radiotherapy combinations potent effect than expected from the summation of in the clinic results from spatial cooperation or additivity. the effects for each agent applied alone. The term ‘radiosensitisation’ is not recommended unless the drug is devoid of any cytotoxic potential. 1 . 1. Quantification of interactions between the drugs and radiations * Corresponding author. Tel.: +33-1-4249-9024; fax: +33-1-4249 4467. E-mail address: [email protected] If the cytotoxic response to the drug or radiation does (C. Hennequin). not folfollow an exponentintial dose dependence, as is the 0959-8049/02/$ - see front matter ## 2002 Published by Elsevier Science Ltd. PII: S0959-8049(01)00360-4 222244 C. Hennequin, V. Favaudon/ European Journal of Cancer 38 (2002) 223–2300 case in most instances, the determination of the addi- 2.1. Additional damage or modification of radio-induced tivity status of the radiation–drug interaction cannot be DNA damagee reached directly from the inter-comparison of the sur- vival curves. Moreover, data from combined treatment Ionising radiation induces a wide range of lesions in consist of three variables, namely the doses of the two the DNA of target cells, including base damage, alkali- agents and the rreessuulltting outcomee.. To overcome tthhiiss labilile ssiittes, ssiinnggllee--ssttrand breaks (SSBB)) and double-- problem, Steel and Peckham [1,4] proposed a method strand breaks (DSB). It has long been shown that these based on the isoeffect concept and relying on the con- lesions are rapidly repaired, with the noticeable excep- struction of isobolograms for any given isoeffect. Actu- tion of DSB for which the tt11//22 for rejoining extends over ally, when the effect is fixed at a given value, e.g. at 10% 5555 mmiin oorr more iinn repaaiirr-proficient cceellllss.. Unrepaiirreedd survival, the system is reduced to two variables so that DSB arare ccoonnssisistetentntllyy rereggaarrddeedd aass leleththaall lelesisioonns [6[6].]. isisoobbololooggrarams fofor ththe cchhoosseenn isisooeeffect may bbee ccoon-n- However, the conttrriibution ttoo induced cceelll kkiilll ooff the ssttrruuccted by plplotottiting ththe ddooses of ththe ttwwo aaggeennttss oonn oxidative stress associated with low-low energy transfer separate axes. radiation (LET) and implying poly(ADP-ribose) poly- The central concept in the isobologram method is the merase for its repair, should not be underestimated [7]. determination of the envelope of additivity delineated Many cchhemothereraappeeuutitic druggss alalssoo tatargrgeett DNAA,, by ‘mode I’ and ‘mode II’ frontiers and within which all creating adducts, SSB or DSB. cciiss-diammino-platinum responseess are deemed ttoo bbee purely additiitive. Briefly,, (II) (cciiss-Pt), for example, exert its cytoxic effect througghh mode I and mode II curves are calculated by the addi- the chelation of guaninnee residues, yielding monofunc- ttiioon ooff responseess ttoo each agenntt applliieed alone, using ttiioonal adducts and iinnttrasttrraand oorr iinntteerrssttrraand crossss-- different regionnss ooff the experimentaall dose–effect rela- links. The bulk adducts are repaired through the exci- tionships. These curves are assumed to represent com- ssiioon repair pathway [[88]], but mmiismatch repair is aallssoo plplete ininddeeppeennddence ooff trtreeaattmmeennttss ((mmoodde II)) oorr exactct involved in the processing of cis-Pt adducts by the cell complementation of the effect of one treatment by the [9]. The possibility exists that the presence in close vici- other (mode II). The data points falling below (above) nity in DNA, of both a cis-Pt adduct and a radiation- the envelope of additivity indicate supraadditive (infra- inindduuceced SSSSB may reressuult iinn a mututuaall iimmppaairmeennt ooff additive) interactionn.. Details ooff the calculationnss have proper repair (Fig. 1). This model is supported by cal- been described elsewhere [5]. culations made to estimate the probability of interaction For a sufficient degree of significance, the construc- between cis-Pt adducts and radiation-induced SSB [10] ttiioon ooff iissoobolograms requuiirreess quannttiittaattive measure-- and by experimental data as well [11]. mentnts. TThhis is oonne ooff ththe lilimmiittss ooff ththe meththoodd. FFoorr EEttooppoossidide is a totoppooisisomererasase IIIIaa ppooisisoonn. IItt aacctsts examplee,, healltthhy ttiisssue rreessponssee may not bbee readdiillyy through the ssttaabbiilliissaattiioon ooff aborrttiivvee cclleeavable com-- ininccoorrppoorratateedd iinn an isisoobbololooggrraam. Morereoovverer, isisoo-- plexes and creates DNA DSB [12–14], notably in telo- bologram analysis requires a careful, precise determina- meres [15], and elicits maximum cytotoxicity in the S- tion of the dose–effect relationship for each agent. This phase of the cell cycle. A supra-additive interaction with is because drug and ionising radiation produce dissim- radiation was demonstrated in concomitant exposure [5] ilar dose–response effects, i.e. the shapes of the survival and in the radiation-induced G2-block [16]. It has been curves are characteristically different. For the same rea- pprrooppoosseedd tthhaatt tthhiiss ssuupprra-a-aadddidititivivittyy reressuultlts frfrom son, the additiitivviitty ssttaatus may vary wwiitthh the iissooeffectct enhanced DNA damage in relation to chromatin con- considered, in such a way that supra-additive interac- formational changes associated with active DNA repair tion, when it occurs, is usually more pronounced at a [16]. low degree ooff survivaall [[55]]. However, most precclliinicalal additivity studies have come from in vitro experiments, 2.2. Inhibition or alteration of radiation damage repair and some caution should bbee takeenn in the ttrraansfeerr ooff these concepts to the clinic. Radiiaattion recoverryy is currently conssiiddered aass the main determinant of the fate of late responding tissue. TThherefofore, ththe uusse ooff ppootetenntt ininhihibibitotorrss ooff rereppaair inin 22.. Molecular mechanisms of interaction combination with radiation, is likely
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