Document vBeOQO90MvwN7r0pkK9Bm5Q5b

... . . .. . .. . - Influence of Carcinogens on the Age Incidence of Leukemia in the High Leukemia F Strain of Mice* .Arthur Kirschbaum, Ph.D.,** and Leone]! C.Strong, Ph.D. YI Treatment sone ............................. :I= 29 108 ...........~ethylcholsnthrencin benzene ' &kthylchdmthrencin benzene$. roi 30 32 .I0 3' :0 .............3,4-&nrpyrcae in benzene ~,:,~.6-Dibenunthrsccne in benzene. j: 12 &nzenc .......................... 29 15 0 17 5 a The p e r i d of skin painting with methylcholan- threne bclore leukemia appurcd was approximately' 130 days, whether treatment was begun at birth or at 35 days of age. The avenge age at which leukemia appeared \vas 134 drys if painting was begun at birth, 162days if it \vas begun at 35 days of age. T h e aver- age at which the disease a p p r c d in the benzpyrenepainted animals was 235 days, after slightly more than 200 days of treatment. If only the fint 33 per cent of the animals to develop leukemia are consided (to make the figures comparable with the mahylcholanthrene group) the number of day of painting rquirirl was 17j, or 40 more than in the mcthykhohnthrcnc group. The latent perid in the Jilwnanthracene group was about d ~ y ~ . Anitnals treated with 3.+benzpyrcnc developed more incdiistiml lyniphourcomas than did those treated with niethylcholanthrcne. Methylcholanthrcne favored the apprance of systemic leukemia in young ani- Among all mice treated by pcrcuuncous application. 53 of the 64 that developed leukemia (Table 111) \ w e frcc of skin tumors, whereas only 8 of thc 1x7treatd TAYL1L1: .\vnw.rcr DAYSOF P.uxnsc PIEW.DISG Lt.c)it l i t \ WITM j DIWERESCT licism~ss Arcram days of painting prccnlino Carcimcn leukemia ......Mcrhylchulanhrcne .134 Jays (30-33 pcr ccnc c l c d ~ ~ u * l .........j,~.knxpyrmc IcukcmL) .175 drp fnr firat 33 pcr cent: :I** .. thyr fur 53 per cent I , ~ , ~ , ~ - D i l ~ i i ~ n t h n c c.3a7e5 clays mice that did not develop leukemia were irm oi titlrsr skin carcinomas or papillomas. In ai1 cases suppiir:itirl;l was associated with the skin cancer. No 1ui.b* tllllltrl were found on gross examination. hlosc ot thr .PI CJH male mice which were treated twice wcckly w i h j.+-l&pyenc tltvetopcil skiit 1iiiiiors. Irut wne ilcvcl- cinogen relatively wore micc din1 of skin tuiiiors olxd lciikciiiia. kiorr mi A y s ut age. I)ibenranthraccne piiitiiig Intr;iveiioiis iirirytion ;it h \vccks oi :tgc ( t i ct.2 Iligiii. iliil not alter the 1:itcrit Iwriml (as iouiid in untrwtcd oi iiicth!lr.hol;inthrr.iie dislwrseil i n Iwsc seruiii tlhl iiiiiwils) for Icukciiiia. The etFccrir.encr3 oi thew not dccrc;ise the latent period ior the dcvclopiici\t of carcinogtns in &creasing this I J k n t p r i d w a s pro- leukemia. Ut' Ij strain F mice SO tratcnl only 0111: portional to their clfwtiventx in producing skiii c:inccr JerelopcJ leukemia bdore 200 days of :lget and this in this strain. w:is the only tiioux of the group to develop lcukeiiiia In studying the intiuence on Icukcnii;t in the F str:iin before joo thp oi age. The ic\cidcrice of sponmneous of an aniticial nongenrtic factor. 3 . p b e n r p y x thus inmiiiiary c;iiiccr in the F strain is las than I pcr ccnt far appears to be the carcinogen of choice since it is (one case in I I j control iemale !mcders), but 3 of (i ktter tolerated than methylcholanthrene ( fewer skin females receiving mcthy1choI;inthrenc intravenously tumors at an early age) and more effective thin derelopd iii:rninmrv cancer. .ill these anitiials had dibenzanthracenc. It has not yet k e n determind lwen :iilowxl to b r e d and rear young. Two of thae whetlier the total incidence of leukemia .in thr: F mmuriarr cmcers appeared a i I!~O days of age. and thc strain can l x iticrrawd b y lo\\*eringthe conccntritioii aniinals were sacrificed at iuH days of age, when the of the solution of lwnzpyrene in benzene. thus pcrh;lp Carcinwea - - - - -MhDIk~ih~nreirthpnhyysyrlicknchltnhtdconi~nc.cnt.h.nn.re.tm.h..rc.$$..c.................................................................... i~tj 30 53 IZ 29 9 IO 4 3 1 I I 5 I I t in 19 14 * 6 ~ o u l r.......................... 181 53 I2 B 109 ' tumors had reached a considerable size. One tumor decreasing the incidence of skin tumors without too \vas an adenocarcinoma, the ochd a squamous cell appreciably affecting the power of the carcinogen to arcinoma. The third mammary cancer, a squamous induce leukemia. cell carcinoma, appeared at 478 days of age. In both Apparently those t m t c d F mice that did not de- squamous cell carcinomas the origin of the cancers velop skin tumors were more susceptible to the induc- could be traced from ductal epithelium. T h e carcino- tion of leukemia than were those that did (Table 111). gen had been injected intravenously into the tail vein, Jr is possible that the development of skin cancer a site distant from the axillary region, in which all the exerted some inhibitory action on the development . mammgry tumors arose. of leukemia, or that the suppuration a.ss0chtcr.i with the skin tumors represents 3n inhibitory mechanism. MSCL'SSIOX In contrast to these findings, however, Engelbrcth- Following the percutaneous application of 34-bent pyrene to mice of the clba strain, Morton and hlider ( I I ) found the latent period preceding the appearance of leukemia to be greater than with methylcholan- threne. T h e incidence of the disease also \vas lower. In the present experiments with the F strain it was found too that thc latent period was longer with j,+benzpyrene than with methylcholanthrene, but the total incidence of.leukemia \\*as greater. T h e latter Holm and Lcfivre (2) hwc obscrvcd that in mice ofthe Ak and Dlb strains painted with g,rodimethyl1,2-&nmnthracene, "no antagonism \vas observed between the occurrence of the painting tumor and the development of mammary carcinoma or leukemia." While the percutaneous application of benzene did not significantly alter the age incidence of leukemia in a group of 29 strain F mice, there is evidence that perhaps this vehicle for the carcinogens can appreciably findings can perhaps bc attributed to the longer latent shorten the preleukemic latent period and increase the period preceding the developnrent of skin tumors in incidcnce of leukemia in the dba strain, although not the F strain when lwnzpyrene rather than methyl- to the same extent as either methylcholanthrenc or cholanthrcnc \vas uxtl. In the case of the latter car- j.+-l~enzpyrcnc ( I I). Morton and XIidcr ( I I ) &o - found that the cnrcinopns wcrt! inore effective when SC.\l.\I.+KY dimlvcd iir lxnzent th:lcr in :icetone. I t is likely that in the series of F micc iciiectrd trith ~ Z C ~ iInCm t n c oil ( ~ j b l c1) $e appearance of leukcmia \\*as ac- cclcntd. but not nearly so decidedly as in animals -T h e rfcicncy of mcth~lcholnnthrent j.;-lXnz- pyrcne. and r.2.S.6.rlibcnt;lnthr;lcene. when Jis%o\...mi in lxnzene and applied to the skin. in hastcnini :!= appearance oi leukemia in the high IeukcmL F receiving methylcholanthrene or 3-+henrpyrcne dis- of mice bore a direct relation to the p o i ~ l ,l,i~ l~hc solved in benzene. , carcinogens in inducing other tumors in t h m mice- In our erpcricnce the response of mice to carcinogens Both methylcholanthrene and benzpyrene were crfrc. with respect to the devclolunent of leukemia has been tive in shortening the preleukemic latent p i u j . in direct proponion to the suxeptibility of each strain methylcholanthrene being the more active in this of mice to spontaneous leukemia (6). In the C3H gard. Dibcnwnthracene did not dccreax the plr. s w i n painting with methylcholanthrene niscd the Ieukemic' latent period. although thu carcinogen d m incidence of leukemia from t per cent (3 of 180 induce skin tumors. The latent perid ( h v c c n inur. a i m a h ) to 33 per cent (3 of 9.1 animals). T h e &on of treatment and the appearance or'leukcmiat &ax in untruted aniilwls appeared when they were was the same whether treatment \vas begun Jt !li::h btwccn 400 and 600 days of age, whereas induced or at 35 days of age. The effect on the app~.l:.-~ leukemia appeared in mice k t w & roo and 300 days of leukemia could be attributed i0 the action or :tc of age (6). Among 39 C3H mice treated similarly amnogens and not to the vehicle, benzme. r 2 c with 3&cnzpyrene no leukemias appeared within m t e d mice which did not derdop skin tumors rcidiir the first 300 days of life. It is of interest that treatment were more susceptible to the induction of leukcmu with appropriate doses of estrogenic hormones raised than thosc which d~~elopcsdkin papilloinv and car& &e incidence of leukemia appreciably in the C3H nomas relatively early. Intravenous injection oi 02 strain (4). In the C3H stock wd by US the estmgem m g m methylcholanthrene at 6 weeks of age did not =present a more potent leukemia-inducing agcnt than influence the age of appearance of leukemia in 1; either methylcholanthreneor 34-benzpyrent Kcither strain F mice, but 3 of 6 f a d e breeders clevcioped thc NH nor $7 strain, both low leukemia st&, inamwry cancer. The incidence of mammary mnccr de\.eiopcd leukemia when crated with methykchob- in untreated female b d e r s of the F strain is !ms thccne (pcrcuuncous application). Other investigators than r per cent. have observed,however, that the incidence ofleukemia can be definitely i n d in certain low leukemia I stocks by treatment with carcinogens (2,7, XI). T h e latent paid between the institution of treat- , ment and the appurann of leukemia was not signifiuntly different, whether percutaneous application \vas bcgun at bd or at 35 &YS OE age. This obscntation is in keeping with the findings o other invcstigafan, who have noted, in addition, that older a h I s am perhaps not 50 responsive to the leukemia-inducing action of carcinogenic agenu as thosc z months ofage 01younger (7, XI). The intnvcnous injection of methylcholanthrcnc did not affect the age incidence of leukemia in the small --- . _.. . - .- .. .-. . . _...... _ . . _. ... , .-..-... .. . .. .. . . . . . . .. . .i . ..