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Induction of Sister Chromatid Exchanges and Chromosomal Aberrations by Busulfan in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia and Normal Bone Marrow1

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Induction of Sister Chromatid Exchanges and Chromosomal Aberrations by Busulfan in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia and Normal Bone Marrow1 (CANCER RESEARCH 48, 3435-3439, June 15, 1988) Induction of Sister Chromatid Exchanges and Chromosomal Aberrations by Busulfan in Philadelphia Chromosome-positive Chronic Myeloid Leukemia and Normal Bone Marrow1 Reinhard Becher2 and Gabriele Prescher Innere Universitäts-und Poliklinik (Tumorforschung), Westdeutsches Tumorzentrum, Hufelandstrasse 55. 4300 Essen l. Federal Republic of Germany ABSTRACT (5) human tumor cell lines and described a correlation between the sensitivity to chemotherapy measured by the colony-form Cytogenetic effects of busulfan in vitro were studied in normal bone ing efficiency assay and the rate of induced SCE. Furthermore, marrow (nine cases) and Philadelphia chromosome (Ph)-positive cells the clonal heterogeneity of chemotherapy resistance within a (10 cases) of patients with chronic myeloid leukemia. The frequency of single solid tumor was evidenced by different levels of induced chromosome aberrations and sister chromatid exchange (SCE) increased dose dependently. While there were no significant differences between SCE (6). normal and leukemic cells with regard to the induction of chromosome Our intention was to analyze SCE induction by therapeuti- aberrations, the frequency of SCE was significantly lower in Ph-positive cally relevant agents in leukemias. Ph-positive CML was chosen cells than in normal bone marrow. This difference was not only apparent for the study presented here because the leukemic cells can on the basis of the SCE frequency per cell, but also when the SCE easily be distinguished from normal cells by means of the Ph frequency was correlated to the relative chromosome length as shown by chromosome. Secondly, SCE and chromosome breaks in nor the SCE rate per chromosome group. Longitudinal studies of three mal bone marrow cells can function as control values. This patients who received long term busulfan treatment did not show a allowed us to assess differences between normal and neoplastic significant change in the frequency of induced SCE. It can be suggested cells of the same tissue origin, which seemed mandatory for the that the lower frequency of induced SCE in Ph-positive cells reveals less interpretation of induced SCE in leukemic cells. sensitivity of the leukemic cells to DNA damage by busulfan. Our data provide evidence for the inability of busulfan treatment to eradicate or In an earlier study we showed that short term cultures and in even reduce Ph-positive cells in chronic myeloid leukemia. Evaluation of vitro treatment with mitomycin C of Ph-positive leukemic cells cell proliferation by sister chromatid differentiation shows longer cell from patients with CML are possible and may yield reproduc cycle times for the Ph-positive cells. Busulfan affected the cell cycle ible results (7). Busulfan has been the most frequently used duration of leukemia and normal cells very little. drug in the routine treatment of the chronic phase of CML for many years. In order to assess its clinical relevance in the treatment of CML, we subsequently investigated the cytoge INTRODUCTION netic effects of busulfan on normal and Ph-positive cells. In SCE3, which occurs spontaneously in proliferating cells, has addition we extended this study to the evaluation of structural been shown to be a highly sensitive parameter for the monitor chromosome aberrations. ing of mutagenic and/or carcinogenic effects (1). Structural chromosome aberrations are also known to be indicators of MATERIALS AND METHODS genetic damage in exposed cells. In contrast to SCE, which occurs physiologically, structural chromosome aberrations such Patients. Normal bone marrow was obtained from healthy bone as chromosome breaks are rare under normal conditions. Since marrow donors who had made marrow available for their siblings for they may lead to random DNA loss in dividing cells, they can bone marrow transplantation (Table 1). Only patients with Ph-positive be lethal. Compared to chromosome aberrations SCE is re CML were considered for the study of leukemic cells. The study was garded as the more sensitive assay (1). performed with cell material derived from untreated patients (six cases, Nos. la, 2a, 3a, 6, 7, and 8; Table 2) at the time of diagnosis or from As chromosome aberrations and SCE mark end points of patients pretreated with busulfan or hydroxyurea who had been off DNA damage, evaluation of both cytogenetic parameters pro cytotoxic treatment for at least 2 months at the time of analysis. Three vides more comprehensive information for the assessment of patients (Nos. 1, 2, 3; Table 2) were studied before and after long term DNA damage (2). busulfan treatment. DNA damaging drugs constitute the largest group of am ¡can Normal bone marrow was obtained by sternal or iliac crest puncture. cer drugs presently in clinical use. Several authors have shown In CML patients, peripheral leukemic cells were also used. The hepa- that many of these drugs can induce SCE as well as lead to rinized cell samples were immediately delivered to the cytogenetic laboratory for further processing. increased chromosome fragility (for review see Ref. 2). Al SCE Studies. Cells were cultured in McCoy's medium which was though differences have been observed in the amount of induced chromosomal aberrations and SCE, the increase of both param supplemented with 20% fetal calf serum (Boehringer, Mannheim, FRG) and gentamicin (Boehringer, Mannheim, FRG) in a concentration of eters has been shown to correlate with the amount of cell kill SO Mg/ml. Cultures were set up in dark-stained glass culture flasks (3). Therefore the level of induced cytogenetic anomalies was which were wrapped with aluminum foil in order to completely protect examined for its value in predicting response to cytotoxic them from light exposure. The concentration of BrdU (Serva, Heidel chemotherapy. Tofilon et al. (4) studied animal and Deen et al. berg, FRG) used, was 10 ¿iM/mlof culture medium. Culture time was SO h for all cases including colcemide treatment (GIBCO, Europe) in a Received 12/30/87; revised 3/15/88; accepted 3/18/88. concentration of 0.1 ^g/ml for the final 2 h. Thereafter cells were The costs of publication of this article were defrayed in pan by the payment of page charges. This article must therefore be hereby marked advertisement in treated with hypotonie KC1 solution (75 IHM) for 20 min, fixed in a accordance with 18 U.S.C. Section 1734 solely to indicate this fact. fresh solution of methanol/glacial acetic acid (3:1), and washed three 1Supported by the Deutsche Forschungsgemeinschaft (SFB 102, A7). 2To whom requests for reprints should be addressed. times in fresh fixative. SCE staining was performed as earlier reported 3The abbreviations used are: SCE, sister chromatid exchange; Ph, Philadel in detail (8). phia; CML, chronic myeloid leukemia; BrdU. bromodeoxyuridine; PI, prolifera SCE Frequency. SCE frequency was evaluated in M 2 metaphases tion index; SCA, structural chromosome anomalies. which had incorporated BrdU during two 5-phases of cell cycle. The 3435 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1988 American Association for Cancer Research. SCE AFTER BUSULFAN IN CML ONi 1 1 1 1 1 1 1 1 \\ l •22 Q9•H ±0.42C*ö00«+100öÕ»osÕ;ö>M»-0>N21.66 5MgsC 28•n 111 1 1 1 M 1 1 in1 +15Q 1111 Ml^i 1 1 1 1 1 1 1 1 1 1 CQ3Busulfan,S1"3 i is i as Ja ERcuo73Mfr- 1 1 1 1 i i 3.Z.NOi°.\ esf>ÕN in m ON 1Sii111 1 — O ON O ON xO C^ON+1 ^ ON O vO 1*- ^t't NO O ^ -H••r+1 1 +1 1 -fi -fi 1 -H +1SÇ|vQ'er*ONNO'm ' m «N fNr- -- 00 fi — fN o1 i^ ^t m +1+1+1+1+1p +11*cüÌ/ÃŒ+1|sli-Q1111 fs-'"D3 IO—»n 10 | o m O|Ors m -fo «soo p fN 1 (N 1 fN ÕS 1 «S0 /bonemarrown \o°2 —oo—ÕN~ oo oo t^- 11 1 r Õr i — r i r i S|t^>n<sr-)o>32 •1 222l83ÕÕOÖ?\ O Ö Ö O O normeä 1§i1's1iJlHiw -^rs.rmo--^•Hm r- —\o m mmoo<n•H-H-H-H-H-H-H-H+I-H—oöSSSSiSSSSSrJ—— |(N M +1S*II»EUQW •?i 00-H00 -HgssNO+1 +1ON+1+1+1+1 +f 11S0HBusulfun. Oo O »N (N ^T fS «nr- oooor-^oo^ocvooooooocSSPSSSK:0Voo r- -e oo oo 03§öu(JC/JUu(JWt/sEL oi—m»n ça§auUuuuäa.Q(N-vO 1=,000^20000SS3S2!plpl_fS (N CS5•* 'fN^iN ——r-ir-io -Hr^~--tí-H -fl -H -H +1 +1 -H +1 r_.(N rriri N !- ^ vo 1- 0 ¡—~_ _ <- -§p— — — ri — sOfiiN^-^fNoors — V}i«1t»1ä!§ ^ T ^ ^ -rp Õm ^Tf>«4î!sio "?|väJi1 cfS lit CNQOOOO—r^ooN —— +|öööööödöö^.o«tnm—— OO — OOO — in >o "~ ^ O-o o5o o o Co O O O O fi mctaph;per <S«OO OOO <00o o o o o o metaphases.°ible ai IIO E ffN s1 12 Chromosomalaberrai —1^1II2 'than10evaluless—, U3OO/Mean *metaphase.Met., fs^\oooooin>o Õ\ 00 OO«fN("1 — <N NO 00 fi 't N±0.15 Iti• valueiions WöijSine3V lio11100öfSp-+1B00inOO 3436 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1988 American Association for Cancer Research. SCE AFTER BUSULFAN IN CML methodology of SCE scoring included so-called peripheral and central chromatid exchanges (9). Each SCE event was specified according to the chromosome group where it occurred.
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