Chromosome Aberrations Induced in Human Leukocytes by the Antileukemic Antibiotic Adriamycin

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(CANCERRESEARCH31, 32â€”38,January19711 Chromosome Aberrations Induced in Human Leukocytes by the Antileukemic Antibiotic Adriamycin

B. K. Vig Department ofBiology, University ofNevada, Reno, Nevada89507

SUMMARY AM), the former has been reported to be about 1.5 times as effective as the latter (9) and also has a higher therapeutic A new antitumor, antileukemic antibioticâ€”adriamycinâ€”is index (1 .21) than DM (0.67)(4, 9). shown to cause chromosomal damage when used on human The influence of minor molecular alterations on the leukocytes in in vitro cultures at concentrations as low as 0.02 chromosome-breaking potentials of several agents has been pg/ml for 24 hr or 0.05, 0.10, or 0.15 j.tg/ml for 3 to 4 hr. well documented. A few examples are 8-ethoxycaffemne versus Aberrations of all conceivable types (intra- as well as 1,3,7,9-tetramethyluric acid (7), 5-fluorodeoxyuridmne versus inter-chromatid, -chromosome , and chromatid-chromosome 5-bromodeoxyuridine (8), modified alkylating groups, and type) are observed. However, a high frequency of modified mustard groups (2). The chromosome-damaging chromosome-type fragments is noticed which compares in potential of DM was demonstrated by this laboratory general with the frequency of chromatid-type exchanges but is (19â€”21), but no attempt appears to have been made so far to higher than the chromatid-type breaks. Asymmetrical carry on such studies with AM. Thus, in view of the structural exchanges are more frequent than symmetrical ones. differences between AM and DM, the higher therapeutic index The distribution of exchange points along the length of of AM, the better therapeutic potential of AM than DM, and chromosome (or group of chromosomes) expresses nonrandom other information provided above, it was considered useful to effect of adriamycin on the chromatin matter. Chromosomes 3 study the effect of AM on human chromosomes with the and Y appear to be far more resistant to the effect of the drug following objectives: (a) to study whether, like DM, AM is than other chromosomes. An analysis of fragments and capable of causing chromosome breaks; (b) to determine what exchanges indicates nonrandomness of the action of the drug kind(s) of aberrations are produced by AM and whether they within chromosomes also. Study of exchanges involving are similar to those produced by DM; (c) to study the specific corresponding points of the members of the exchange complex points of breaks and exchanges along the lengths of individual show that adriamycin perhaps does not induce somatic chromosomes and to compare their distribution with what is crossing over to any considerable extent. These observations known for DM. agree with those made on a sister drug, daunomycin (daunorubicin). MATERIALS AND METHODS INTRODUCTION The studies were carried out by using human peripheral AM' was isolated from Streptomyces peucetius var. caesius whole blood in microcultures as described by Moorhead et aL in 1967 by Arcamone et al. (1) at the Farmitalia Research (10) with chromosome Medium lA (Grand Island Biological Laboratories, Milan, Italy. The drug has since been found to be Co., Berkeley, Calif.). AM was received from Farmitalia composed of an aglycone chromophore (adriamycmnone) Research Laboratories as a gift for research. For all linked to an amino sugar (Chart 1). It is closely related to experiments described here, AM was dissolved in distilled another antibiotic, an antileukemic drug, DM (or water. Cells were treated with AM, 0.02 pg/mI (final daunorubicin)(l4, 18). concentration), during the last 24 hr of culturing to see AM has been recently shown to have antileukemic, whether aberrations originate with such low doses. In further antitumor properties in tests with mice in which Ehrlich experiments, the final concentrations of the drug were 0.05, ascites carcinoma, ascitic transplantable lymphosarcoma, solid 0.10, and 0.15 pg/mI, applied between 44 and 48 hr of sarcoma, and solid Oberling-Guerin-Guerin carcinoma (9) were culturing. In all cases, cultures were treated with Colcemid, 0.2 used and with human children and adults against acute 11g/ml (final concentration), at the end of 72 hr, unless lymphoblastic, chronic myelogenous leukemias, malignant otherwise stated, and cells were fixed 3 hr later. For analysis lymphomas, neuroblastomas, and soft-tissue sarcomas (4). of the points of breaks and exchanges along the length of Although AM differs from DM only in the replacement of a chromosomes or groups of chromosomes, the cells from 3 hydrogen (on the acetyl radicle of DM) by an hydroxyl ion (in different experiments treated with 0.05 pg/mi of AM between 44 and 48 hr of culture period were used. In all short-term

I The abbreviations used are: AM, adriamycin; DM, daunomycin; experiments, the medium was changed once or twice, and cells CC,guanine-cytosine. were kept at 37Â°for about 20 to 24 hr to accomplish recovery ReceivedMay 14, 1970; accepted September 18, 1970. and to collect metaphases.

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For scoring of aberrations, the standard criteria were used. complement. A point of emphasis was the study of homologs Gapsâ€”small achromatic discontinuities seen along the length (orapparenthomologs)whichhadexchangedsegmentsatthe of chromatid or chromosome without disturbing the corresponding positions in the nonsister chromatids. These can continuity of the chromosomeâ€”were not included in the be scored in the first metaphase after the origin of analysis. Isolated fragments (or breaks) were of chromatid aberrations studied here because the chromosomes involved type if only 1 of the 2 chromatids was broken or deleted at are still held together in a â€œchiasma-likeâ€•configuration. The any one point; where both chromatids were affected, the 2 figures presented in the paper are only representatives of sister fragments were classed as 1 chromosome fragment. aberrant cells, usually severely affected, and were not Exchanges and intrachromosomal reunions were classed as necessarily used for analysis of positions of breaks or chromosome or chromatid type, depending upon whether the exchanges. origin could be traced to a single-stranded or double-stranded chromosome(s). Thus, dicentrics and rings were considered as chromosome exchanges (or reunions) whereas triradials were RESULTS classed as chromatid exchanges. Sister unions, both proximal and distal, were treated under a separate class because of their The pilot experiment conducted by using AM, 0.02 pg/mI different kinetics of origin. (final concentration), during the last 24 hr of culture clearly For the analysis of chromatid exchanges and fragments exhibited the potentials of the drug in bringing about regarding their points of origin along the chromosome, only chromosomal aberrations. Out of a sample of 110 cells chromosomes or fragments were used which could be analyzed at metaphase after administration of the drug, a large definitely identified to a particular chromosome or a group of majority (92 out of 110, i.e., 83.6%) had chromosomal chromosomes. The analyzable fragments were in the vicinity aberration of one kind or the other. These aberrations (Fig. 1) of the parent chromosome and their point of origin. The include fragments and exchanges of both chromatid and points of chromatid breaks were easily recognized because of chromosome type. One class of interest was the triradials with the intact ,position of the sister chromatid. Approximate single, 2, or very rarely 3 centromeres in the whole complex. positions of breaks were marked along the lengths of reference Usually, centromeres in excess of 1 were located 1 on each lines drawn to represent the lengths and positions of chromosome participating. Some of the monocentric triradials centromeres of the chromosomes (or groups) in the were extremely small and appeared to have originated by intrachromosomal manipulations. The origin of these 0 OH monocentric triradials will be discussed elsewhere. Of the other aberrations (Table 1), the most predominant are the chromatid-type exchanges which constitute 37.6% of all OH aberrations. Next in order are the chromosome fragments (28%), and chromatid-type fragments make up 17.7% of the total. The last class discussed constitutes only a fraction of the O@H3 chromatid-type exchanges which, according to classical â€œbreakagefirstâ€•hypothesis (1 5, 17), are only a secondary consequence of the phenomenon giving rise to chromatid-type fragments. Aberrational frequency in the untreated control (Table 1) was extremely low. The frequency of asymmetrical (u-type) exchanges was

HO higher in the material treated with 0.02 pg/ml than that of NH2 H symmetrical (X-type) exchanges from the same material. Out of 100 chromatid exchanges analyzed, 63 were asymmetrical Chart 1. Molecular structure of AM. and only 37 were symmetrical. These observations confirm the

Table 1 Frequenciesofchromosome aberrations induced by AM Concentrationaberrations/cellChromatidChromosomeChromatidChromosomeSister(pg/ml and frequency of of drugTreatmentintervalNo. of cellsAberrantType (%)fragmentsfragmentsexchangesexchangesunionsTotal0.00Control1004AM)(hr)scoredcells

(4.0)0.020.000.010.010.000.040.00Control1003 (3.0)0.000.020.000.010.000.030.0248â€”7211092 (83.6)0.330.911.270.090.433.030.0520â€”2411256 (50.0)0.180.410.320.030.121.060.0544â€”4810671 (67.0)0.330.660.740.040.252.020.05 (51.6)0.060.660.220.040.071.05Few 0.1044â€”48mitosesâ€”0.1044â€”481108020â€”2415580 (72.7)0.230.860.550.040.352.030.1544â€”4811090 (81.8)0.721.171.650.040.253.83

JANUARY 1971 33

B. K. Vig

large deviation from expected 1: 1 (x2 6.76; dc 1; p > OOl) asobservedinalmosteveryinstancedealingwith such analysis. As assurance that chromosome aberrations were not really the manifestation of the chromatid-type aberrations duplicated during the 2nd cell cycle, the aberrant cells were reclassified from qualitative aspects. There was only 1 cell with chromosome exchange(s) without at least 1 accompanying chromatid aberration. The 20 cells (out of 92) with only chromosome fragments (and no other aberration) had a mean frequency of 1.05 fragments against an overall frequency of FRAGMENTS 2.1 for cells with at least one fragment besides other aberrations. Also, about 73% of the cells had chromatid-type exchanges. To confirm the chromosome-damaging potential of AM and to see whether continuous treatment as given in above experiment yields different results from a short-term U treatment for a few hr, we treated the cells with 0.05 and 0.10 pg/ml of culture between 20 to 24 hr and also with 0.05 pg/ml during 44 to 48 hr of culturing. Cells were harvested 24 hr later. The results (Table 1, Rows 4 and 5) confirm the observations made earlier. However, 2 different individuals were the donors of blood for these experiments: a male for 20- to 24-hr treatment experiment and a female for the 44- to 48-hr treatment experiment. In both these experiments, the cells without chromatid exchanges or fragments were very rare

l1@ S 0 c'4 v, (â€˜4 (â€˜4 (â€˜4 -.- cz c â€˜-â€˜ -â€˜- (â€˜) @ â€” (â€˜4 4.,

Total 9 U 2 13 38 20 11 3 5 0 Chart 3. Points of breaks inferred from fragmentation along the length of human chromosomes.

and the frequency of chromosome-type fragments approxi mated the frequency of exchanges. The type and frequency of aberrations and the relationship between aberrations were also studied on a blood culture from EXCHANGES a male with 0.05, 0.10, and 0.15 pg of AM/mi of culture medium during 44 to 48 hr of culturing. The results (Table 1, Rows 6, 8, and 9) indicate dose dependent frequency of aberrations. Here again, the most predominant aberrations are the chromatid-type exchanges and chromosome-type fragments. Furthermore, an increase in concentration of the U drug causes a rapid increase in the proportionate frequency of chromatid-type exchanges. Thus, whereas these exchanges constitute about 21% of the total aberrations when cells are treated with 0.05 i.ig/ml of the drug, the proportion goes up to 27% with 0.10 pg/ml treatment and to as high a figure as 43% El when cells are given 0.1 5 pg AM/ml. The positions of chromosome breaks and exchanges were analyzed from 3 samples treated with 0.05 pg/ml between 44 and 48 hr of culturing. It was found that these positions, at least qualitatively, were similar to one another. Hence, the

v, â€¢ 0 Cl data were pooled to give composite diagrams for the points of breaks inferred from exchanges (Chart 2) and for breaks @ Cl (@) 4 @2 ! inferred from fragments (Chart 3). The frequency of a Total 14 19 5 24 Hi 28 24 4 11 0 chromosome or a group of chromosomes in 120 exchange Chart 2. Points of breaks inferred from exchanges along the length of figures analyzed has been summarized in Table 2. human complement. Chromosome 2 is involved more often than any other

34 CANCER RESEARCH VOL. 31

Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 1971 American Association for Cancer Research. AM-induced Chromosome Aberrations chromosome in absolute frequency, but it was Group G Even if there is not an exact 1-to-I correspondence between (2 1/22) that participated most often per unit length. Y the frequency of breaks per unit of chromosome length in case chromosome was the only one which was not involved in any of exchanges versus fragments, the data appear quite similar in exchange. Group C was engaged maximally in intragroup most respects. Thus, in both the cases, the Y chromosome and exchanges, i.e., exchanges involving both the chromosomes Chromosomes 3 and 19/20 are the least involved. from the same group. As shown in Table 3, the involvement of That the breaks are not localized only in the various chromosomes was not uniform or dependent upon heterochromatic part of the chromosomes is of interest. their length but was rather nonrandom. One obtains a similar However, in this case, unlike that ofDM, the aberrations were idea from Chart 2, which indicates a nonrandom distribution found in and around the areas of centromeres (proximal of the points of exchanges, a certain area along the length of heterochromatin) also. chromosome being much more susceptible to breakage than Reciprocal Exchanges between Homologous Chromosomes. others. Table 3 indicates the relative frequency of breaks per In studies conducted with exchange points, special attention unit of chromosome length. was given to the identification &f the exchanges involving A total of 112 points of chromosome b reaks were analyzed homologous chromosomes at corresponding points. This might from fragments (Table 3). The distribution ofpoints of breaks indicate that somatic crossing over had occurred. Although along the length of chromosomes or groups thereof (Chart 3) there were as many as 37.5% of the exchanges observed which does not support the contention that breaks are nonrandom involved homologous or apparently homologous along the length of the genome. Also, the frequency of chromosomes, only 8 out of 120 exchanges involved exactly break points per unit of chromosome length in this case does corresponding loci. These were as follows: 4/5 group, 1 not compare well with the respective values for exchanges. exchange; 6-l2/X group, 4 exchanges; 16/18 group, 1

Table 2 AMSecondFirstAnalysisofchromosomes involved in exchangesinducedby 0.05 @&g/mlof chromosomeschromosomes chromosomes or group of orgroupofTotalchromosomes1234/56-12/X 21/22Yexchanges1222213300004/5111366-12/X311313326213/1521121113/15 16/18 19/20

21916/1812004 31619/2000001 6 0321/2210001 0 2 29Y00000 1 3 1 000Total121651849 0 0 0 20120exchangesTotal1419524111 9 8 1

110240chromosomes 28 24 4

Table 3 genomeChromosomeFrequency distribution ofexchange points and chromosomebreaksalong the length ofthehuman

orExchangesBreaksObservedObservedPerPergroup of chromosomesTotalunit(total)X21141.6320.672.1591.059.640.042192.3619.350.01111.379.030.43350.7416.307.8320.297.604.134/5241.9928.970.85131.0813.520.026-12/X1113.1485.107.88381.0739.110.0313/15282.5326.560.08201.8012.404.6616/18242.8220.430.62111.299.530.2319/2040.8711.064.5030.655.160.9021/22113.497.571.5551.593.530.61Y00.003.973.9700.001.851.85Total24024029â€¢44b11211212.90â€•lengthExpected(totala)x2Totalunit lengthExpected

aBasedon the complement 2A +11'. bdf = 9;p < 0.001. Cdf Â°9;0.20 >p >0.10.

JANUARY 1971 35

Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 1971 American Association for Cancer Research. B. K. Vig exchange; and 21/22 group, 2 exchanges. These data do not DM and is more potent as an antileukemic agent, it may be express preferential breakage and reunion at corresponding desirable to compare the chromosome-breaking potential of points on homologous chromosomes and may not thus the two. It remains to be seen how, under similar experimental support the idea that somatic crossing over had occurred. conditions, the 2 drugs compare for type and frequency of aberrations. However, the present study can give some insight into the comparative mechanisms of induction of aberrations DISCUSSION by comparing the qualitative as well as quantitative aspects of the points of breaks along the length of the genome as induced It is clear from the foregoing experiments that AM can by the 2 drugs. The data summarized in Charts 2 and 3 cause chromosome aberrations in quantities as low as 0.02 indicate the relative inertness of Chromosome 3 and Y when pg/ml (2 parts per hundred million). Even brief exposures of AM is used as mutagen. This is in good correspondence with the duration of 3 to 4 hr with concentrations between 0.05 to the results published earlier for cells treated with 0.01 5 pg/mI 0.10 pg/mi are capable of triggering the chromosome breakage of DM (23). Equally comparable, both qualitatively as well as mechanism. However, the drug expressed differential influence quantitatively, is the incidence of breakage of the groups 4/5, on the cultured cells when the latter were treated between 20 6-l2/X and 13/15 in the 2 cases studied. However, and 24 hr or 44 to 48 hr. Repeatability of these results should Chromosomes 1, 2, 16/18, and 21/22 are examples of be of interest as a help in understanding the timings and mode differences observed in the 2 experiments. Chromosomes 21 of action of the drug. and 22 are involved more frequently in breakage and The frequency of chromosome breaks was always higher exchanges with AM than when the cells were treated with DM. than the frequency of chromatid breaks but in general parallel Also, the proximal heterochromatic areas are seen to be more to the frequency of chromatid exchanges. There were very vulnerable to the action of AM. This is no guarantee, however, few, if any, exchanges of chromosome type. It is hard to of the differential potency of the 2 drugs on human visualize that what are being considered here as chromosomes because, in the 2 experiments compared, the chromosome-type fragments are really isochromatid fragments cells were treated with different doses of the 2 drugs and also because then their frequency should not be higher than the at times different in the 2 cases. That such differences can be frequency of chromatid fragments and the frequency of sister expected even when the cells are treated by the same drug has unions should have something in common with the been amply demonstrated by Ockey (11), who treated Vicia chromatid-type exchanges. The data do not support either faba roots with I X l0@ ethyleneimine contention. It may then indicate that the drug is capable of (triethylenemelamine). The involvement of positively causing breaks to the G, chromosomes at a time when heterochromatic regions was maximal at early times (1 2 to 20 reunions are not easily accomplished and that the exchanges, hr) with localization becoming progressively less marked in certainly a majority of them at least, do not reflect a later samples (28 and 36 hr). Also, the involvement of breakage-reunion type of sequence as suggested by classical Chromosome 5 declined in favor of Chromosome 1 with an hypothesis of origin of chromosome aberrations (17). On the increase of recovery period. These results might indicate the other hand, the relationships between the 2 types of fragments differences in the physiological activity of the cell rather than do not support the alternative hypothesis of fragmentation those of individual chromosomes per se since the treatments through incomplete exchanges as proposed by Revell (13) were carried out with a single dose of the chemical. Besides, when the data in Table I are taken at face value. The logical there are quite a few reports now available which indicate that explanation may be that both the mechanisms (the classical closely related chemicals may have entirely or quite different and the exchange type) are contributing to the formation of effect on chromosome structure and morphology. these aberrations. Such analysis has been made by Heddle and 1,3-Propanesultone, shown to be a chromosomal mutagen (6), Bodycote (5) for chromatid breaks obtained in mitosis of is capable of producing a significant propox@tion of deletions irradiated Vicia faba. and duplications, whereas the related 13-propiolactone rarely, if The distribution of break and exchange points along the ever, produces these types of aberrations. chromosomes strongly indicate that heterochromatic areas are There appears to be no preferential exchange formation not the sites of preferential â€œattackâ€•bythe drug. Although between the homologous chromosomes at corresponding the related drug, DM, does bind to purines (24) and although points. Only 8 out of 120 exchanges gave any indication that heterochromatic zones have been suggested to be rich in somatic crossing over had occurred. In this regard also, AM guanine-cytosine content, it does not mean that the appears to be similar to DM (23). These results appear to be chromosome-breaking action of such chemicals is through different from what is known about mitomycin C (8, 12, 16). their influence in guanine-cytosine-rich regions. The drug may As a matter of fact, one must depend upon some genetic change to a somewhat different molecule in the cell before it marker(s) to establish with certainty that reciprocal exchange acts as a chromosomal mutagen (7). The true test will lie in at corresponding points of 2 homologous chromosomes has correlating the points of breaks with the sites to which the taken place (22). drugs may bind on the chromosomes. The action of AM, anyhow, differs from several molecules of known mutagenic ACKNOWLEDGMENTS potency, e.g., alkylating agents (7), streptonigrin (3), and mitomycin C (12 , 16). I am thankful to the Farmitalia Research Laboratories, Milan,Italy, Inasmuch as AM is structurally somewhat different from for the gift of AM.

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REFERENCES 13. Revel, S. H., and Natarajan, A. T. Somatic Association in Relation to Chemically Induced Chromosome Aberrations in Vicia faba. Genetics, 57: 821â€”835,1967. 1. Arcamone, F., Franceschi, G., Tenco, S., and Selva, A. 13. Revell, S. H. The Accurate Estimation of Chromatid Breakage and Andriamycin (14-Hydroxydaunorubycin), a Novel Antitumor Its Relevance to a New Interpretation of Chromatid Aberrations Antibiotic. Tetrahedron Letters, 13: 1007â€”1010,1969. Induced by Ionizing Radiations. Proc. Roy. Soc. London, Ser. B, 2. Caspersson, T., Zech, L., Modest, E. J., Foley, G. E., Wagh, U., and 50: 563â€”589,1959. Simonsson, E. Chemical Differentiation with Fluorescent 14. Rusconi, A., and Calendi, E. Asione della Daunomicina sulla sintesi Alkylating Agents in Vicia faba Metaphase Chromosomes. Exptl. Nueleica in Cellule di Epatoma. Tumori, 50: 261â€”266,1964. CellRes.,58:128â€”140,1969. 15. Sax, K. An Analysis of X-ray Induced Chromosomal Aberrations in 3. Cohen, M. M., Shaw, M. W., and Craig, A. P. The Effect of Tradescantia.Genetics,25: 41â€”68.1940. Streptonigrin on Cultured Human Leukocytes. Proc. Nail. Acad. 16. Shaw, M. W.,and Cohen, M.M.Chromosome Exchangesin Human Sci. U. S., 50: 16â€”24,1963. Leukocytes Induced by Mitomycin C. Genetics, 51: 181â€”190, 4. Di Marco, A., Gaetani, M., and Scarpinato, B. Andriamycin 1965. (NSC-123, 127): A New Antibiotic with Antitumor Activity. 17. Stadler, L. J. The Experimental Modification of Heredity in Crop Cancer Chemotherapy Rept., 53: 33â€”37,1969. Plants, I. Induced Chromosomal Irregularities. Sci. Agr., 11: 5. Heddle, J. A., and Bodycote, D. J. On the Formation of 557â€”572,1931. Chromosome Aberrations. Mutation Res., 9: 117â€”126,1969. 18. Theologides, A., Yarbro, J. W., and Kennedy, B. J. Daunomycin 6. Kaul, B. L. The Production of Chromosomal Aberrations by Inhibition of DNA and RNA Synthesis. Cancer, 21: 16â€”21,1968. Propanesultone in Viciafaba@Mutation Res., 7: 339â€”347,1969. 19. Vig, B. K. Alterations in the Pattern of Daunomycin Induced 7. Kihlman, B. A. Biochemical Aspects of Chromosome Breakage. Chromosomal Aberrations by Inhibitors of Protein and DNA Advan. Genet., 10: 1â€”59,1961. Synthesis. Mutation Res., 9: 607â€”614,1970. 8. Kihlman, B. A. Actions of Chemicals on Dividing Cells. Englewood 20. Vig, B. K., Kontras, S. B., and Aubele, A. Sensitivity of G1 Phase Cliffs, N. J.: Prentice-Hall, Inc., 1966. of Mitotic Cell Cycle to Chromosome Aberrations Induced by 9. Monfardini, S., Bonadona, G., DiPietro, S., Guindani, A., Daunomycin. Mutation Res., 7: 91â€”97,1969. Fossati-Bolani, F., and De Lena, M. Sperimentazione cinica 21. Vig, B. K., Kontras, S. B., Paddock, E. F., and Samuels, L. D. preiminare con Adriamicina in Pazienti Affetti da Leucemia e Daunomycin Induced Chromosome Aberrations and the Influence Tumori solidi mi fase Avansata. Tumori, 55: 197â€”216,1969. of Arginine in Modifying the Effect of the Drug. Mutation Res., 5: 10. Moorhead, P. S., Nowell, P. C., Meilman, W. J., Battips, D. M., and 278â€”287, 1968. Hungerford, D. A. Chromosome Preparations of Leukocytes 22. Vig, B. K., and Paddock, E. F. Alteration of Leaf Spot Frequencies Cultured from Human Peripheral Blood. Exptl. Cell Res., 20: in Glycine max (L.) Merrill by Mitomycin C. J. Heredity, 59: 513â€”616,1960. 225â€”229,1968. 11. Ockey, C. H. Chromatid Aberrations Induced by Ethyleneimines. 23. Vig. B. K., Samuels, L. D., and Kontras, S. B. Specificity of Erwin-Bauer-Gedachtnis-Vorlesungen I. Abhandl. Deut. Akad. Daumomycin in Causing Chromosome Aberrations in Human Wiss. Berlin K!. Med., 1: 47â€”53,1960. Leukocytes. Chromosoma, 29: 62â€”73,1970. 12. Rao, R. N., and Natarajan, A. T. Somatic Association in Relation to 24. Ward, D. C., Reich, E., and Goldberg, I. H. Base Specificity in the Chemically Induced Chromosome Aberrations in Vicia faba. Interaction of Polynucleotides with Antibiotic Drugs. Science, Genetics, 57: 821â€”835,1967. 149:1259â€”1263,1965.

JANUARY 1971 37

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Fig. 1. Examples of different types of aberrations induced by AM. A, chromosome acentric fragments and 1 sister union (proximal); B, dicentrics (arrows) resulting from chromosome type of aberrations; C, chromatid exchanges and other types of aberrations; D, a â€œdemolishedâ€•cell where the identity of individual chromosomes is totally lost; E, chromosomes with highly deformed morphology (note the exchange point at arrow); F, 2 daughter nuclei connectedby a persistentbridge of chromatin and 2 micronuclei presumably resulting from acentric fragments.

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Downloaded from cancerres.aacrjournals.org on October 5, 2021. © 1971 American Association for Cancer Research. Chromosome Aberrations Induced in Human Leukocytes by the Antileukemic Antibiotic Adriamycin

B. K. Vig

Cancer Res 1971;31:32-38.

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