Apoptos is and Tum or

6 4 V o l. 6 N o. 4 1997 12 H ENAN M ED ICAL RESEA RCH D ecem ber 1997 Apoptos is and Tum or ( 450052) 1,,,,, : ;,,,,,,, 60, Kerr ( sh inkage necro sis) [1 ], (necro sis),, Kerr 1972 (apop to sis) [2 ], apop to sis, [3 ],,,,, (p rogramm ed cell death),,,,, 80,,,,,,, 2 : :, ; :, 211 [4, 5 ] : 21111 :,,,,,, 21112 :, (apop to t2 ic body),,,,, 21113 :, 366

4 367,,,,, [6 ],, (residual body),, (autophagic vacuo le),,,, (acri2 dine o range),, RNA,, DNA [7 ], ( term inal deoxynucleo tidyl transferase, TD T ), DNA, DNA, DNA, TD T, [8 ] TD T, DNA, TD T DNA, TD T,,, (trypan blue) 3 1. 2., 3., 4. 5. 6. 212,,,,, H E,,,,,,, Feulgen, W yllie [9 ],, Ca 2+ M g 2+, A rends [10 ], H 1, DNA DNA 180 200 bp, (ladder pattern), DNA ( topo iso2 m erases) DNA DNA,, ( transglutam inase),,,, [11 ],

368 6 (apop to sis) (necro sis),, HE,,,,,,,, TDT 3,, DNA,, DNA,,,,,,,,,,,, A TP DN T 180 200bp, (P I), (G1), G1, 3,, A TP DNA,,,,,,,,, DNA [7 ], Eh rlich,,,,, Kerr Eh rlich, DNA,, DNA, DNA,, DNA,, DNA,,, : (TN F) M nsod TN F Hockenbery [12 ] bcl22 4,, : 411 p53 p 53 p 53 p 53 (w tp 53), p 53 (m tp 53) w tp 53,, w tp 53, DNA, w tp 53 DNA, p 53, G1, S, DNA,, p 53 WA F - 1 [13 ] p 21, (CD K), CD K,, DNA m tp 53 w tp 53, w tp 53,,, DNA S, 412 bcl-2 bcl22 B, V aux [14 ] bcl22,,

4 369, bcl22, bcl22 bax bcl2x bad [15 ] bax bcl22 bax bcl22 bax bcl22 bcl2x, bcl2x l bcl2x s bcl22, bax, bcl22 413 c- myc cm yc,, c- m yc,,,,, c- m yc, : (c - m yc, ); (c- m yc, ) (c- m yc, ) [16 ] m tp 53 bcl22 c- m yc 414 Ced, Ced- 3 Ced- 4, Ced- 3 Ced- 4 Ced- 9 [17 ] Ced- 3 21Β ( Ice) M iura [18 ] Ice, Fas 1 Ice, Ice Cpp 32, Ced- 3 Ich- 1 Ich- 2 Ice Ice 415 FasgApo- 1, p 53 bcl22 C- m yc FasgA po- 1 Fas A po- 1,, FasgA po- 1 T (SC ID ),, FasgA po- I T, 5,, = -,,,,, T Co lum bano [19 ] (DM H ), 1% Α2AA F,,,,,, [20 ] DM H,,,,, [21 ], g, 6, 611,,, : DNA, ;, ;, D

370 6 ;,, ;, stau2 ro spo rine okadaic acid;,, ;, [7 ] D C Eh rlich,, 13% 3 h, D 1718% 1714%, 14% 12 h 28% 37%, 24 h 4311%, C 40102%, D 3717%, 4111% Eh rlich,,,, 4- N -, 612,, 43, 30 m in,, 46 30 m in, [22 ] [23 ] Eh rlich, 37 41 43 30 m in, 37 12 h, 41 43, 41 2615%, 43 3117%, 37 1312% (A gnor s), 41 43, 37,, 37 DNA,,, DNA, 613,,,, Co lom bel [24 ], bcl- 2, bcl- 2, bcl- 2, bcl- 2, W arri [25 ] To rem ifene, To rem ifene,,,, [22 ] 614 Stephens [26 ] Χ - () ( ) 6 h 20%, 3%,, Χ-, 5 6 [27 ] X EL - 4,, X EL - 4, EL - 4 X, DNA, EL - 4, G1, p 53 bcl- 2 c- m yc 615 T K N K [22 ] [28 ] L ak, L ak,, T, T DNA, T, Ca 2+, Ca 2+, DNA [29 ]

4 371 7,,, 95%,,,, Am es DNA,,,,,, H eddle [30, 31 ] (m i2 cronuclei),,, [32 ] C 57BL DM H ( ), 24 h,,, H eddle C 57BL,,,,, [33 ] [34 36 ], DM H,,, DM H [37, 38 ] 8 Kerr 1972,,,, ;, 1 Kerr JFR. Sh inkage necro sis. A distinct mode of cellular death. J P athol, 1971; 105: 13 2 Kerr JFR, Currie A R. A basic bio logical phenom enon w ith w ide- J Cancer, 1972; 26: 239 ranging imp lications in tussue kineticṡ B r 31 1 :.. :, 1982: 47 4 Kerr JFR, B ishop CJ, Searle J. A pop to sis. In A nthony PP, M acsw een RNM eds. Recent A dvances in H istopatho logy. London: Churchill L ivingstone. 1984: 1 5, 1 (apop to sis) 1, 1992; 11: 150 6 Savill J, T adok V. Phagocyte recognition of cells under2 go ing apop to sis. Imm unol T od ay, 1993; 14: 131 71 1[ ]1 1, 1989: 37 8 Go ld R, M usk P, W hellon A, et al. D ifferentiation be2 tw een cellulr apop to sis and necro sis by the com bined use of situs tailing and nick translation technique. L ab Inves, 1994; 71: 219 9 W yllie A H. Glucoco rtico id induced thymocytes apop to2 sis is associated w ith endogenous endonuclease activa2 tion. N atu re, 1980; 284: 555 10 A rends M J, M o rris RG, W yllie A H, et al. A pop to sis the ro le of the endonuclease. A m J P athol, 1990; 139: 593 11 Fesus L, T hom azy V. Search ing fo r the function of tis2 sue transglutam inase: Its po ssible invo lvem ent in the biochem ical pathw ay of p rogramm ed cell death. A d v E xp M ed B iol, 1988; 231: 119 12 Hockenbery DM, O ltval ZN, Yin AM, et al. Bcl- 2 functions in an antioxidant pathw ay to p revent apop2 to sis. Cell, 1993; 75: 241 13 el- D eiry W S, Toknmo T, V elculescu V E, et al. WA F 1, a po tentialm ediato r of p53 tumo r supp ression. Cell, 1993; 75: 817

372 6 14 V aux DL, Co ry S, A dam s JM. Bcl22 gene p romo tes heamopo ietic cell survival and cooperates w ith c- m yc to immo rtatize p re2b cells. N a tu re, 1988; 335: 440 15 Bo ise L H, Gonzalez GM, Po stem a CE, et a l. bcl- X, a bcl22 related gene that functions as a dom inant regular of apop to tic cell death. Cell, 1993; 74: 597 16 Evan G I, W yllie A H, Gilbert CS, et a l. Induction of A pop to sis in fibroblasts by c - 1992; 69: 119 m yc p ro tein. Cell, 17 E llis HM, Ho rvitz HR. Genetic contro l of P rogramm ed cell death in the N em atoded C. elegans. Cell, 1986; 44: 817 18 M iura M, Zhu H, Ro tello R, et a l. Induction of apop to2 sis in fibroblasts by 1L - I beta- converting em zym e, a m amm alian homo log of the C. elegans cell death gene Ced- 3. Cell, 1993; 75: 653 19 Co lum bano A L edda- Co lum bano GM, Rao PM, et a l. O ccurrence of cell death (apop to sis) in p reneop lastic and neop lastic liver cells. A m J P a thol, 1984; 116: 441 20 1, 1992; 11: 345 211 1 [ ] 1 1, 1997: 62 22 Kerr JFR,W interfo rd CM, H armon BV. A pop to sis. Its significance in cancer and cancer 1994; 73: 2013 therapy. Cancer, 23, 1 Eh rlich., 1995; 30: 153 24 Co lom belm, Symm ans F, Gil S, et a l. D etection of the apop to sis supp ressing oncop ro tein Bcl22 in ho rmonerefracto ry hum an p ro state cancers. A m J P athol, 1993; 143: 390 25 W arri AM. A pop to sis in To rem ifene- induced grow th inh ibition of hum an breast cancer cells in vivo and in vitro. J N a tl cancer Inst, 1993; 85: 1412 26 Stephens L C, A ng KK, Schultheiss T E, et a l. A pop to2 sis in irradiated m urine tumo rs. R ad iat R eṡ 1991; 127 (supp l) : 308 27,,. EL - 4., 1995; 21: 449 28,,, 1 1, 1992; 1: 20 29 Sh iver JW, SU LQ, H enkart PA. Cyto toxicity w ith tar2 get DNA breakdow n by rat basophilic leukem ia cells exp ressing bo th cyto lysin and granzym e A. Cell, 1992; 71: 315 30 H eddle JA, B lakey DH, D uncan AM V, et al. M icronu2 clei and related nuclear anom aliea as a sho rt- term as2 say fo r co lon carcinogenṡ In: B ridges BA. Butterwo rth BC, W einsitein IB eds. Indicato rs of Geno toxic Expo2 sure. Banbury Repo rt: 13. Co ld Sp ring H arbo r L abo ra2 to ry. 1982: 467 31 Ronen A, H eddle JA. Site- specific induction of nucle2 ar anom alies ( apop to tic bodies and m icronuclei) by carcinogens in m ice. Cancer R es, 1984; 44: 1534 32,,,. 1, 1991; 13: 171 33,,. 1, 1994; 3: 104 34,,, 1 1, 1991; 26: 17 35,,, 1 1, 2 1, 1992; 14: 255 36,.,, 1992; 4: 12 37 1 2 1, 1991: 13: 120 38 Yin PZ, Zhao JY, ZHU Q F, et al. Experim ental studies of the inh ibito ry effects of green tea catech in on m ice large intestinal cancers induced by 1, 2- drazine. Cancer L ett, 1994; 79: 33 dim ethylhy2 : 1997206205 Am J Cardio l 1997; 79: 341, Gradm an, 707 (enalap ril) 5 m g 20 m g (felodip ine extnd2 ed- release) 2. 5 m g 5 m g 10 m g, 8, 4,, ( ), (10. 8% ); ( 2. 2% 2. 3% ) 1997 8 14 7