18
日泌 尿 会誌, 85巻, 11号, 1994年: 1575~15921575 前 立 腺 癌 腫 瘍 マ ー カ ー-PSAを 中心 に一 倉敷中央病院泌尿器科 TUMOR MARKER IN PROSTATE CANCER Yoichi Arai Department of Urology, Kurashiki Central Hospital は じめ に 前 立 腺 癌 の 診 断 の 主 力 は1980年 代前 半 まで は,直 腸 診(digital rectal examination, DRE)と, 前 立 腺 酸性 ォス ファター ゼ(PAP)で あ っ た. し か し優 れ た マ ー カ ー で あ る前 立 腺 特 異 抗 原(prostate specific antigen, PSA)の臨床 応用 の確 立 と経直 腸超 音波 断層 法(transrectal ultrasonography, TRUS)検査 のルー チン化 によって前立腺癌の診断 ・治療 をめ ぐる状況は した とい って よ い. す な わ ち 前 立 腺 癌 を め ぐ る臨 床 に も よ う や く科 学 的 な 環 境 が 整 っ て き た と い え よ う.特 にPSAは そ の 名 称 が 示 す よ う に,前 立 腺 の 組 織 異抗 であ り, そ の 臨 床 的意義の重要性 と有用性 と い う点 か らみ れ ば 他 臓 器 癌 の 腫 瘍 マ ー カ ー で は類 を み な い. PSAは これ ま で 内外 で 精 力 的 に検 討 さ れ,PAP に 代 わ る第1位 の 腫 瘍 マ ー カ ー と して 臨 床 応 用 が ほ ぼ に確 され る. 本 論 文は前立腺癌腫瘍マー カー全 につ いて の概 を意 図す もので る. しか し現 時点 で のPSAの 要性 を考慮 し て, PAPな ど他 のマーカーについてはその歴史 と役割について簡単に 触 れ る に と どめ た い. 一 方, PSAに つ い て も こ れ ま で 優 れ た 総 説 は す で に多 数 発 表 さ れ て い る1)~6). 従 って その歴史的背景や生化学的特徴 などについてはごく簡 に 述 べ, 前 立 腺癌 を 日常的 に取 り扱 う泌 尿器 科医 を 念 頭 に お い て 最 近 のPSAの 臨 床 的 意 義 や 問 題 点 に焦 点 を あ て つ つ概 説 を進 め た い. PAP を診 し, ま た その病勢 をモニターす るための血 清 腫 瘍 マ ー カ ー を 見 つ け る た め の研 究 は古 くか ら な さ き た. 前 立腺癌 にお ける酸性 フォス ファターゼ (AP)はそ の よ うな マ ー カ ー と して 最 初 に 実 用 化 さ れ もの あ る. APが 前立腺癌患者血清で上昇してい る こ と を 報 告 し た の は1936年Gutman7)が 最初であ る. し か しAPは 他 の臓 器 に も広範 に存 在 す る酵 素 で り, し た が っ て他 の疾患 で も血清 中の上昇 が しば し ば認 られ, 前 立腺への特異性が低いことが問題で あ っ た8). 当 初,前 立 腺 性 酸 性 フ ォ ス フ ァ タ ー ゼ(PAP) の 測 定 は 酵 素 法 す な わ ち生 物 学 的 活 性 の 違 い に よ っ て 他 のAPと 区 別 す る 方 法 が 用 い られ て い た8). 1970年 代 に 入 っ てimmunoassay法 れ, 現 在は radioimmunoassay(RIA)法 ま た はenzymeim- munoassay (EIA)で測定 され てい る9)10). こ のim- munoassay法 に よって癌 の検 出 率 はや や上 昇 した と され た が, 1980年, PSAが 登 場 す る に い た り, PAPの 腫 瘍 マ ー カ ー と し て の 意 義 は 急 速 に 失 わ れ つ つ あ る.PAPは 前 立 腺 癌 腫 瘍 マ ー カ ー と し て, そ の 治 療効果判定や経過観察においてなお有用性が報告され てい る が, 早 期 診 断 に お け る 限 界 は す で に 明 らか で あ ろ う11)12). PSA PSAは そ の 名 称 が 示 す よ う に 前 立 腺 上 皮 で 特 異 的 に産 生 され る糖 蛋 白で あ る. そ の 分 子 量 は34, 000で240 ミノ 酸 と4本 の糖 り成 って る. ア ミノ 酸 構 造 か らproteaseで あ るkallikreinフ ァミリーに属 して い る と考 え られ て い る13)~16). PSAはchemotr sinまたはtripsin様 の酵素活性を持っていることが る17). こ こ と が 最 近 のPSA- antichemotripsin結 合体の臨床的研究へ発展してく るこ とにな る が, こ の 点 に つ い て は 後 述 す る. PSAは 理的 作用 につい はい まだ不 な点が い が, 精 漿 中 に はmg/m1単位 の高濃度 で存在 し18), 精漿液凝固 物質の液化 に関係 して い る と さ れ て い る1)17). PSAを コー ドす る遺伝 子 は6kilobaseサ イ ズ で,第19番染 色 体 上 に 存 在 し て い る こ と もす で に 明 らか に な っ て い る19).

前立腺癌腫瘍マーカー-PSAを 中心に一 - J-STAGE

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Yoichi Arai

1980 ,
(digital rectal examination, DRE),
(PAP) .
(prostate specific
antigen, PSA)
(transrectal ultrasonography, TRUS)

.

. PSA ,
,

. PSA , PAP
1
.
.
PSA , PAP

. , PSA
1)6).

,
PSA
.
PAP
,

.
(AP)
. AP
1936Gutman7)
. AP
,
,
8). , (PAP)

AP 8). 1970
immunoassay ,
radioimmunoassay(RIA) enzymeim-
munoassay (EIA) 9)10). im-
munoassay
, 1980, PSA ,
PAP
. PAP ,

,
11)12).
PSA
PSA
. 34, 000240
4 .
protease kallikrein
13)16). PSAchemotrip-
sin tripsin
17). PSA-
antichemotripsin
, . PSA
,
mg/m1 18),
1)17). PSA
6kilobase , 19

19).
1576
, γ-seminoprotein 21). 1973
Li and Be1ing22)
, EI antigen . 1978
Sensabaugh p30
23). 1979, Rosewll Park Memorial
InstituteWang13)
PAP ,
.
(PSA) .

14)24), PSA
.
1. PSA
Wang13) PSA ,
PSA Ros-
ewl1ParkMemorialInstitute
. 1980 Papsidero25)
,
PSA , PSA
.
(rocket immunoelectrophoresis) ,
PSA 8%
. Kuriyama26),
enzyme immunoassay(EIA) ,
PSA ,
PSA .
PSA cut-off 1. 8ng/ml
. cut-off PSA
(BPH)68% , stage
, A; 63%, B; 79%, C; 77%, D; 86%
.
PSA kit 1984,
Hybritec Tandem-RPSA 27).
Yang radioimmunoassay(RIA)
Pros-Check-PSA 28). ,
.
PSA ,

.
kit PSA ,

1)2)6). 29)
1984 EIKENPA(RIA)
, Kuriyama30)MARKIT-FPA
(EIA) .
PSA
2).
PSA kit10
,
2)6). PSA

. PSA
,
. assay
,
Kuriyama31) .
, PSA
32). 1991
PSA
, PSA
.
, PSA
, PSA
31). , Stamey1992 PSA
,
2). 1994 2
,
.
II. PSA
Oesterlingl) ,
PSA ,
. , , ,
, PSA
.
PSA ,
Tandem-RPSA Pros-CheckPSA

.
Maatman33) PSA
7. 6% ,
. PAP PSA
34). 6)PSA
,
. PSA ,
24 18%
3).
PSA
1577
35), PSA
, 36).
PSA . Stamey3)
Pros-Check PSA , 2. 2±0. 8
. , 0esterling37)Tandem-
RPSA 3. 2±0. 1
. Kabalin38) PSA
,
.
PSA ,
(DRE)
. Brawer39)DRE
, PSA
. Stamey40), DRE PSA
(Pros-CheckPSA)1. 92
. , DRE PSA
Tandem-RPSA randomized study
41). DRE PSA
,
0. 4ng/ml . DRE
PSAcut-off4. Ong/ml
. TRUS PSA
42).

. PA-TESTWAK0 BPH
, DRE PSA
2. 5 43). , MARKIT-
MPA
44). , PSA

45),
6).

PSA .
PSA ,
PSA
42). Yuan42) PSA
. PSA
, 25%
, PSA
, .
PSA 46)47).
PSA
.
III. PSA
PSA
1)2).
Tandem-RPSAPros-Check
PSA .
IMxDainapack(EIA)
48), 49).
PSA EIKEN
PA MARKIT-F PA .
1. cut-off
PSA Cut-off
, .
Tandem-R PSAPros-Check PSA cut-off
, 4. Ong/ml50), 2. 5ng/m13)
. ,
50 2 cut-
off 1. 9ng/m1, 3. 2ng/m1
2). , PSA cut-off ,

, PSA
. MARKIT-FPA
3. 6ng/ml cut-off 30),
MARKIT-MPA
44). EIKEN PA 29)3. 0ng/m1
. , BPH
,
BPH , BPH
cut-off
44)51). PSAcut-off

,
. cut-off

. , TRUS systematic
biopsy ,
52).
, cut-
off .
PSA
51)53)55). PSA
cut-off
52)55). Dalkin55)Tandem-RPSA
PSA
. Tandem-R PSAcut-off4. 0
1578
ng/m160
.
2. BPH PSA
PSA
, BPH PSA
. BPH
775%
1)2)44)51).
cut-off ,
PSA
1)2)6). Oesterling1),
Tandem-RPSA ,
BPHPSA 4 .
BPHPSA4. 0ng/m1
72% , 28% .
BPH PSAcut-off
4. Ong/ml 70%
. BPH
PSA
. Stamey3)Pros-CheckPSA
, BPHlg PSA0. 3ng/ml
. , Weber56)
, 5. 816. 6
, PSA
. ,
, BPH PSA0. 2ng/ml
10ng/ml
57).
, Weber
.
BPHPSA
46)47).
(intraepithelial neo-
plasia) . Brawer58),
Lee59)
, PSA
.
, .
PSA
, 1
. PAP
, PAP PSA
43)51)62)63). stageC
PSA
43)51).
PSA , stageD
90% 62)63). , PSA
, PSA
. PSA
,
,
PSA 64). PSA
PAP
6)30)65).
,
,
.
3. PSAdensity
BPH PSA
,
PSA PSAdensity
(PSAD) 66)67). Benson66)61
1 PSA stage
BPH PSAD .
PSAD0. 1 34 33 ,
0. 050. 111 6 , 0. 05 16 2
, .
, , PSA
, PSAD
2). Rom
mel68), 2, 020
PSAD .
PSAD
, PSA

PSAD . PSAD

, .
4. PSA
, mass
screening( )
. PSA
massscreening
2)30)63). , PSA

,
,
.
systematic biopsy
. 6
(
) , PSA

. , 69) PSA
, PSA
.
PSA
70) 71)
.
,
PSA
72)75). Cooner75)
DRE, PSA, TRUS
,
. PSA
(Tandem-RPSA)cut-off
. PSA4ng/m1 ,
4. 110ng/ml, 10. 1ng/ml , 3
. 1
Cooner75)
. PSAcut-off
TRUS
,
.
5. PSA velocity
Caretr76)
PSA
. BPH
, 826
PSA ,
. ,
PSAvelocity(PSAV)
. PSA
.
, PSAVcut-off 0. 75μ9/1/year
, specificity90%
77). PSAV
BPH
,
.
IV. PSAstaging
Stamey78)
, PSA
(r=0. 7) .
1g PSA3. 5ng/ml
1 (
. , McNeal79)

. PSA patho-
10gicalstage
78)80).
PSA
(2)80). PSA10ng/m1
,
SUrgiCal margin .

PSA
. ,
PSA ,
1)64)80).
Oesterling 1) , cut-off 4ng/ml 10
ng/ml ,
72%, 24% ,
55%, 13% . Stamey81)
, PSA transitionzone

.
PSA
,
.
clinical stage C
82).
PSA
. ,
64)80). Greskovich83),
stageC
PSA 11. 4ng/ml, 11. 2ng/ml
. staging pe1-
vic lymphadenectomy PSA
(MARKIT-F PA), Gleason score
. PSA10ng/ml
Gleason score 6
. , PSA 10ng/ml
Gleason score7 60%
(3)80).
PSAGleasonscore
84). Partin85)703
, PSA(Tandem-R PSA), Gleason score,
pathological stage
,
, .
3 pathological stage
.
Gleason score 5 PSA10. Ong/m1
10% . EIKEN PSA
2 PSA(MARKIT-F PA)pathol0gi-
cal stage( ).
LN, . SV, . CP,
. (80 )
+ Surgical margin
3 PSA(MARKIT-F PA), Gleason score
( 80 )
LN (-) LN (+)
86) , PSA20ng/ml
22
2(9%) .
PSA negative
predictive value .

staging operation87)
PSA
.
PSA
Chybowski88) . 521
, PSA
.
, PSA(Tandem-RPSA)20ng/m1 306
1
. PSA
negativepredictivevalue99. 7%
, PSA
1).
V. PSA
PSA

. PSA , , ,

.
1.
PSA
. ,
, ,
PSA ,

1)57). PSA
, PSA
,

1)37)57)78)89).

PSA . PSA
,
.
,
57)90).
,
90).
,
(2). Tandem. R
, 0esterling37) 0. 07ng/
ml . Hudson90)
, Tandem-R
0. 6ng/m1 .
Pros-Check , 0. 10. 5ng/
ml 1). , ,
,
PSA

. MARKIT M-PA
assay ,
0. 2ng/ml 57).

PSA ,
.
PSA
. ,

PSA
57)78). cut-off
,
. Stamey78)Pros-Check ,
2 PSA cut-off
1582
PSA
, cut. off
0. 3ng/ml . ,
0. 3ng/ml ( )
.
Lange89)Tandem-R 59
, 36 PSA0. 4ng/ml
91% NED ,
. PSA0. 4ng/ml 100%
. Hudson90) Tandem-R
, 89%
0. 6ng/m1 ,
cut-o 0. 6ng/ml
. MARKIT-M PA
, 0. 4ng/m1
cut-off
(2)57).
cut-off .
PSA ,
. Lange
89), Tandem-R cut-off
0. 4ng/m1 ,
1243 ( 23 ) PSA
, .
, PSA
,
8 (4)57). ,
Graves91), Pros-Check
72 assay .
cut-off
0. 1ng/ml , ,
Pros-Check 5
PSA ,
. PSA ,
,
.
PSA
, .
PSA ,
, clinica1
failure PSA "biochemica1
failure" . Frazier92)
, PSAclinical failure
2228( 16) ,
. , 11 PSA 36
clinica1 failure ,
PSA
. bio-
chemical failure
,
.
.
2.
PSA
. PSA

. Stamey93)
183( 5) ,
PSA 11%
, . 82% PSA
1 , 1
8% . 1
51%PSA . Hudson90)
, PSA
17% . Kaplan94)
PSA ,
44% , . D'
4 PSA(MARKIT-M
PA) . assay
(MARKIT-F PA)
( 57 ).
Amico95) biochemical failure92)
PSA .
PSA (PSA doubling time, PSA-
DT)
.
PSA
, PSA
. Link96), PSA
, 60%PSA
, . Hudson97) PSA
(Tandem-RPSA)0. 6ng/ml 21
, 29%1 PSA
, .
,
.
3.
Kuriyama98), Killian28)stageD2
PSA
. PSA
28)98). , 99)
PSA
. PSA

100).
PSA
,
. Stamey
101) PSA
, 6
, . 99) 1
6 PSA nadir
, . Arai100)
, PSA
, 1 PSA
(
3). 102), 7 PSA
50%
, . , PSA

, 103). Csapo104),
,
PSA
. Leo105)
PSA ,
PSA
. Morgan
106),

1 ( 100 )
1584

,
111).
PSA
.
PSA .
VI. PSA
PSA ,

112). ,
, PSA
. Stamey78),
PSA
, , .
Lange113) 5% PSA ,
. Hortin112) 92 3
(3. 3%)PSA1. 0ng/ml ,
.
. PSA
114), PSA
. Graves115)
14% PSA
, . PSA
78).
, Pummer116), stageT3
Pros-Check PSA , 6
, 4 9. 527. Ong/ml
, . 3
Tandem-R
. PSA α-
1-antichemotripsin
45). 116),
PSA , α-1-antichemotripsin
, Pros-Check
1
. , PSA
(MARKIT-M PA)
. MARKIT-M PA2
,
MARKIT-F PA (
). PSA
,
PSA . .
VII. PSA
PSA ,

,
117)119). PSA
. ,
PSA
119). Kamoshida
120)cloaca PSA
, PSA
121).
PSA
,
. Sakai122)PAPPSA
,
PAP , .
, Deguchi123)
,
.
VIII. PSA
PSA ,
.
PSA Tremblay
124) . , PSA BPH
, .

. PSA
38),
PSA
. White125) 77%
PSA ,
,
. , Takayama121)
PSA
. , PSA
PSA
, PSA
, .
PSA
.
IX. PSA
Stenman45), Lilja126) PSA
protaeaseinhibitor α1-
antichemotrypsin(ACT) (PSA-
1585
ACT) .
, PSA, PSA-ACT
,
45)126)127). , BPH PSA
,
PSA-ACT
. , PSA
.
Christensson128)
55% 73%
. 129)PSA-
ACT EIA ,
. γseminoprotein
, assay
PSA
130)131). Demura
131)PSA γ-seminoprotein
, PSA/γ-seminoprotein
.
PSA
, ,
,
, .
X. PSA stage
PSATRUS
, stage
132). ,
DRE PSA

. stageA B
,
. ,
0rgan Systems Coordinating Cen-
ter(OSCC) 133). Stamey
, PSATRUS
stageA , stage TAX
(4)134).
stage
,
.
, Wang13)PSA
10 .
Oesterling1) review ,
priority γSm
. γ-Sm
1985 135),
136).
Shidal1137)
. γ-Sm PSA ,
PSA
136). , γSm PSA

51)63)136)138).
130)138). γ-Sm
assay PSA
,
130)131).
, PSA
. Schaller24)Lundwall14)
, PSA γ-Sm
. 136) ,
PAP 3
,
.


.
, alkaline
phosphatase139>140), LDH141), polyamine142), CEA143)'
4 0SCC ( 134) )
1586
creatinine kinase BB144)145), osteocalcin146)147),
.
,
PSA
. PSAPAP
.

, PSA
. PSA
,
. ,
,
. ,
, ,
PSA ,
. PSA
.
,

.

1) Oesterling, J. E.: Prostate specific antigen: A critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J. Urol., 145, 907-923, 1991.
2) Kuriyama, M.: Prostat-specific antigen as a tumor marker in prostate cancer. Int. J. Urol., 1, 99-113, 1994.
3) Stamey, T. A., Yang, N., Hay, A. R., McNeal, J. E., Freiha, F. S. and Redwine, E.: Prostate- specific antigen as a serum marker for adenocarcinoma of the prostate. New Engl. J. Med., 317, 909-916, 1987.
4) Lange, P. H. and Brawer, M. K.: Serum
prostate-specific antigen: Its use in diagnosis and management of prostate cancer. Urology, 33, 13-17, 1989.
5) Brawer, M. K.: Prostate specific antigen. A review. Acta Oncol., 30, 161-168, 1991.
6) , , , :
(
): PSA. , 4, 1065-1072, 1991.
7) Gutman, E. B., Sproul, E. E. and Gutman, A. B.: Significance of increased phosphatase activity of bone at site of osteoblastic metastases secon- dary to carcinoma of the prostate gland. Am. J. Cancer, 28, 485-495, 1936.
8) Pontes, J. E.: Biochemical markers in prostate cancer. J. Urol., 130, 1037-1047, 1983.
9) Cooper, J. F. and Foti, A. G.: A radioim-
munoassay for prostatic acid phosphatase; I. Methodology and range of normal male serum values. Invest. Urol., 12, 98-102, 1974,
10) Lee, C. L., Wang, M. C., Murphy, G. P. and Chu, T. M.: A solid phase fluorescent immunoassay for human prostatic acid phosphatase. Cancer Res., 38, 2871-2878, 1978.
11) Rubenstein, M., Guinan, P. D., McKiel, C. F. and Dubin, A.: A review of acid phosphatatse in the diagnosis and prognosis of prostatic cancer. Clin. Physiol. Biochem., 6, 241-252, 1988.
12) Kontturri, M.: Is acid phosphatase (PAP) still justified in the management of prostate cancer? Acta Oncol., 30, 169-170, 1991,
13) Wang, M. C., Valenzuela, L. A., Murphy, G. P. and Chu, T. M.: Purification of a human pros- tate specific antigen. Invest. Urol., 17, 159-163, 1979.
14) Lundwall, A. and Lilja, H.: Molecular cloning of human prostatic specific antigen cDNA. FEBS, Lett., 214, 317-322, 1987.
15) Chu, T. M., Kawinsky, E., Hibi, N., Croghan, G., Wiley, J., Killian, C. S. and Corral, D.: Prostate-specific antigenic domain of human
prostatespecific antigen identified with mono- clonal antibodies. J. Urol., 141, 152-156, 1989.
16) Lilja, H. A.: A kallikrein-like serine protease in prostatic fluid leaves the predomnant seminal vesicle protein. J. Clin. Invest., 76, 1899-1903, 1985.
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20) , , , ,
, :
( VII).
, 159, 356, 1989.
21) : “γ-Seminopro-
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