- Email: [email protected]
10 Immunomodulation by anticancer agents
A'Ustra(:ts
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RAI)IATION ASSOCIATED "FIIYROII)('ANCER Katsutaro Shinlaoka. M D Radiatiun Effec:ts Research l-'cmnclation, Nagasaki, Japan.
Variuus epidemiologic studies and clinical screening data of irradiated 13ersor~s indicate an inc:reased risk of dew,qoping both benign and malignant thyroill diseases. Experimental animal studies also confirm the causal relationship elf irradiation and thyroid diseases. The majority fff radiati{m-asso(:iated thyroid c a r c i n o m a is '.veil differentiated, either papillary, fclllicular. o r mixed variety, and ()ill}' rarely allaplastig; (:ar(:illtln)a. Medullary (:arc:inolua is seldon'l associated with previ{ms radiation exposurI~ Nuna{! nf the { harac:teristics of radiation-assclciated fllyroid car( in(Jnlil art! a high pr{!valence [}1 nlinimill (uc:t;uh} car(:inoI{la aud the frequenl {:o(!x:ist{!nt:e {if (libel pathcllogic t/ndillgS su(:h as ctflloid nudules. Hmmic: lymphtmytit: thyroiditis, etc. A lhyrcfid-sc:reening prcl,e,ram was started at RPMI by Intblic cienlalld in 1t377, \~,'e act:rued 74.'3 subiec:ls during the first year with later additions to a Intal of approxinmtely lt]O0 bv 1985. (')ne h u n d r e d ti|ty-nille (22.1%] were found lu have palpable atln{irmalities during the first year: subsequent annual st:reenin~, l o u n d 507 (33.8".,,] in total bv 1980. "I'he maiority (431} of these llatieots partil:ipided in a douhh>hlind study to C:olnpare the e{fe¢:tiveness of Imlhyronine (T3] and desiccated thyroid (DT) ill shrinking the goiter. At tile end ot ti months o1 treatment. 7!) (18.3".,,} bad ¢:unlplete disappearance (CR] of palpable abnormalities confirnmd hy sonar, ram. There has been no signifi{.ant difference in the respcmse rate betv,'een T3 and DT. Thus far. 144 haw~ u n d e r g o n e surgery and 32 {22.2%1 were found to have carc:inunm j2]. :\tonlic Bcunb Casualty f;onunission-Radiaticm Effects Research Foundation has previously published several reports on thyroid c a r c i n o m a in A-bomb survivors from both cities, l limshima and Nagasaki: an lilt{eased ini:idence (11 tbvroid carcinolna ilmllllg the exposed was filund. Xl{~rt~ re{:ently, we l . o k e d at the Nagasaki a d u h health stutiy lmpulation, w h i c h is folhn.ved biennially 13]; 285ti suhiects were seen d u r i n g the XIII {:?.'~.leand 1.q c:ases fff thvrccid c:arcinotna have been .~muld thus far.
REFERENCE 1. DeGrocJt LI, t"rohn~an I,A. Kaplau El., P,efetoff S, eds (1!)77): P,adiation-associated Ihyrcmt t:art:inoma (,rune and S t r a i t ( m , New York. 2. Razac:k ,",IS. Shimaoka K. Sake K. Ran U (I!JSP,): mill I Surg 156:2~-HI. :3. l lirayu tt. Izumi M, Tnyama K. Shinlaoka K, Nagataki S ( l~,h~$t~]:VIII Inlernaticmal ('onfereru:e on Endut:rinolugy. Abst #12-19-128.
10
IMMUNOMODUI,ATION 13Y ANTIC'ANCER AGENTS E. Mihich. (,ra{:e Cancer Drug Center. Roswell Park Menlorial Institute. 666 Elm Street, Bur|ale. NY, 14263.
Antiprolih:rative a n d cytotoxic antieant:er agents were initially found to inhibit {:ell-mediated and.'or hu, nmral ilnnmnn responses 11]. In rec:ent years it has become apparent that several uf tiles{," agellts nlav induce an a u g m e n t a t i u n (if certain i m n m n e responses u n d e r certain conditions anti may in fact he defined as having immunI~mudulating activity 12, 3]. While cyc:hlphosphamide inhibits prec:ursors uf T-suppressor cells I4. 51 other agents have diffe, renl selnl:tive a(:li(uls on tile i m m u n e system 12, 3. t5 81. In this report the i m m u n o m o dulating action of a d r i a m y c i n {ADM) is briefly dist:ussed as an example [9-11 ]. The differentiation of mac:rophages into phagocytic: 1!t. 121 or killer [13.14] {:ells is augnlented by ADM in C57H1,'6 mice. M a c r o p h a g e p r o d u c t i o n of such factors as 1I,-1 [14, 15]. TNF 116]. or PCJEz 191 is also stimulated hy the drug. Ill this strain ut mice, using PS1,5 as the allc.antigen. CTL responses ;','ere a u g m e n t e d by the drug given 5 days clr more before antigen in vivo or ex v i l e ¢)r early after antigen in vitro 19, 17. 181. This a u g m e n t a t i o n was associated with the inhibition of a plastic adherent T-regulatory cell and tile increased production of IL-2 [19,201. NK {:ell activity in PEC ',,,.'asaugmented anti in spleen inhibited by AI)M [14,151. Using syngnneic El,4 l y m p h n m a , tumor-associatect depression of l u m t m c i d a l C:TL. LAK cell, NK cell. and killer nlacrophages activities was found to be prevented ill mice given AI)M 5 days prior to t u m o r implantalion 121 ]; this effect was also seen w h e n an Al)M-resistant subline of EL4 was used 122], Therapeutic effects against this resistant suhline were noted w h e n AI)M was given in combination with IL-2 or It,-2 plus I,AK cells [23]. As i m n l u n o m o d u l a t i o n by ADM was also seen ill cancer patients given a single dose of drug 124] it may be pussibh: to develop clinical protocols exploiting this property of the drug toward therapeutic advantage. Tile studios with AI)M sunmlarized herein also support the (:uncept that antineoplastic drugs may be exploited as tcst~fcd tools ill basi¢: studies of illcnlun{lnlodulalion.
8
Abstracts
REFERENCES 1. Mihich E (19711: NCI Monograph 34:90-102. 2, E h r k e M [ , Mihich E(19841: Reticulnendothelial Svstem 8:309 347. :~. Ehrke MI. Mihich E (1985): Trends Pharmacol Sci e.:412 -t17. 4. Cowens el al. (1984): ] l m m u n n l 132:95-100. 5. Smith II, et al. (1987): Meth Find Exp ('lin Pharmacul 9:555-568. 6. Ryoyama K, et al. (1982): Int l l m n m n o p h a r m a c o 1 4 : 1 8 7 194. 7. Schlaefli E. et ill. (1983}: I m m u n o p h a r m a c o l o g y 6:187 122. 8. Ehrke MI, el al. (1988): Cancer Res 46:2798-2803. 9. Ehrke Nil. et al. (1982}: Immunol Re,.' 65:54 78. 10, Ehrke MI. Mihich E (1984): Clin Immunol Allergy 4:259 278 11 Mihich E. et al. [1985}: Biol Respons Cancer 3:71-94 12. Cohen SA, el al. (1982): l m m u n o p h a r m a c o l o g y 5:75 84. 13. Salazar D. Cohen SA [lg8"t): Cancer Res 44:2561 2566. 14. Mace K, el al. (19881: Cancer Res 48:130 136 15. Cohen SA. el al. (1983): Cancer l m m u n o l I m m u n o t h e r 15:188-193. 16. Macc~ K. et al. [1986): Leukocyte Biu 38:68. 17. Tnmazic V. el al. {1980): Cancer Res 4 0 : 2 7 4 8 - 2 7 5 5 18. Tomazic V. el ill, (1981): Cancer Res 41:3370 337(i. 19. Ehrke MI, et al, {19841: Cancer Res 4 4 : 2 4 9 7 - 2 5 0 4 211. Ehrke M], et al. 119881: Cancer Rc~s 4 6 : 5 4 - 6 0 21, Ehrke MI. et al. (19881: Pruc AACR 29:412. 22 M a c c u b b i n D, et al. {1987}: Proc Xth Intl Congress Pharmacol P1325, 23. Mihich E (1988}: Proc AACR 29:517-518. 24. Arinaga S, el ill (1986): Cancer Res 4{i:4213 4216.
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ANTITUMOR IMMUNE RESPONSES FOLLOV¢ING CHEMOTHERAPY IN RATS. Masuo Hosokawa. Cancer Institute, Hokkaido University School of Medicine. Sapporo 060, Japan,
It is well k n o w n that c h e m o t h e r a p e u t i c drugs suppress the host i m n m n e responses. We have observed that therapeutic effects of c h e m o t h e r a p e u t i c drugs w o u l d be improved if the antitumur i m m u n e responses could tm restored or a u g m e n t e d following c h e m o t h e r a p y We examined a n t i t u m o r i m m u n e responses of tumur-bearing rats following c h e m o t h e r a p y in order to find out the correlation of therapeutic effects and the host i m m u n e responses against t u m o r cells. It ',','as found that the a n t i t u m o r i m m u n e responses were strongly suppressed in tumor-bearing rats after a singh; administration of c y c l o p h o s p h a m i d e (CY, 40 mg,'kg i.v.). Combined use of an i m m u n o s t i m u l a t o r y proteinb o u n d p o l y s a c c h a r i d e (PSK, 300 m g / k g / d a y i.p.) not only prevented the CY-induced i m m u n o s u p p r e s s i o n but also improved the therapeutic effects of CY. Our experiments also showed that antitunlor i m m u n e responses of tunlor-bearir~g rats wt;re a u g m e n t e d by an appropriately timed administration of bh:omycin (BLM). We have found the therapmltic effects of BI,M arc; d e p e n d e n t on the timing of its admirtistration after the t u m o r implantation. The therapeutic effects of BLM (5 m g ; k g / d a y i.p. for 5 days} was greater w h e n it was administered from 8 days after the t u m o r implantation (late BLM) than w h e n it was administered 1 day after the implantation (early BLMI. The a n t i t u m n r i m m u n e responses were examined by m e a s u r i n g tumor neutralizing activity and cytotoxic T l y m p h o c y t e (CTL] activity after the mixed l y m p h o c y t e t u m o r culture (MI,TC) of spleen cells. The responses were found to be a u g m e n t e d by late BI,M, but not by early BLM. These findings indicate that the therapeutic: effects of BLM arc; closely correlated with the a u g m e n t e d antitumor i m m u n e responses following the BLM treatment. The m e c h a n i s m s for the a u g m e n t e d a n t i t u m o r i m m u n e responses are s h o w n to be the elimination of suppressor T-lylnphncyte activity induced in the tumor-bearing rats and the activation of macrophagemediated cytotoxity by BLM. REFERENCES 1. A k i y a m a l. el al. (1977]: Cancer Res 37:3042-3045. 2. Morikawa K. et al. (1985): Cancer Res 45:684 688, 3. Morikawa K, et al. (1986): Cancer Res 46:1502-1506, 4. Xu Z-Y, et al. [1986): Cancer Immunol I m m u n o t h e r 23:46- 50. 5. Xu Z-Y, et al. Cancer Res [in press].
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RAI)IATION ASSOCIATED "FIIYROII)('ANCER Katsutaro Shinlaoka. M D Radiatiun Effec:ts Research l-'cmnclation, Nagasaki, Japan.
Variuus epidemiologic studies and clinical screening data of irradiated 13ersor~s indicate an inc:reased risk of dew,qoping both benign and malignant thyroill diseases. Experimental animal studies also confirm the causal relationship elf irradiation and thyroid diseases. The majority fff radiati{m-asso(:iated thyroid c a r c i n o m a is '.veil differentiated, either papillary, fclllicular. o r mixed variety, and ()ill}' rarely allaplastig; (:ar(:illtln)a. Medullary (:arc:inolua is seldon'l associated with previ{ms radiation exposurI~ Nuna{! nf the { harac:teristics of radiation-assclciated fllyroid car( in(Jnlil art! a high pr{!valence [}1 nlinimill (uc:t;uh} car(:inoI{la aud the frequenl {:o(!x:ist{!nt:e {if (libel pathcllogic t/ndillgS su(:h as ctflloid nudules. Hmmic: lymphtmytit: thyroiditis, etc. A lhyrcfid-sc:reening prcl,e,ram was started at RPMI by Intblic cienlalld in 1t377, \~,'e act:rued 74.'3 subiec:ls during the first year with later additions to a Intal of approxinmtely lt]O0 bv 1985. (')ne h u n d r e d ti|ty-nille (22.1%] were found lu have palpable atln{irmalities during the first year: subsequent annual st:reenin~, l o u n d 507 (33.8".,,] in total bv 1980. "I'he maiority (431} of these llatieots partil:ipided in a douhh>hlind study to C:olnpare the e{fe¢:tiveness of Imlhyronine (T3] and desiccated thyroid (DT) ill shrinking the goiter. At tile end ot ti months o1 treatment. 7!) (18.3".,,} bad ¢:unlplete disappearance (CR] of palpable abnormalities confirnmd hy sonar, ram. There has been no signifi{.ant difference in the respcmse rate betv,'een T3 and DT. Thus far. 144 haw~ u n d e r g o n e surgery and 32 {22.2%1 were found to have carc:inunm j2]. :\tonlic Bcunb Casualty f;onunission-Radiaticm Effects Research Foundation has previously published several reports on thyroid c a r c i n o m a in A-bomb survivors from both cities, l limshima and Nagasaki: an lilt{eased ini:idence (11 tbvroid carcinolna ilmllllg the exposed was filund. Xl{~rt~ re{:ently, we l . o k e d at the Nagasaki a d u h health stutiy lmpulation, w h i c h is folhn.ved biennially 13]; 285ti suhiects were seen d u r i n g the XIII {:?.'~.leand 1.q c:ases fff thvrccid c:arcinotna have been .~muld thus far.
REFERENCE 1. DeGrocJt LI, t"rohn~an I,A. Kaplau El., P,efetoff S, eds (1!)77): P,adiation-associated Ihyrcmt t:art:inoma (,rune and S t r a i t ( m , New York. 2. Razac:k ,",IS. Shimaoka K. Sake K. Ran U (I!JSP,): mill I Surg 156:2~-HI. :3. l lirayu tt. Izumi M, Tnyama K. Shinlaoka K, Nagataki S ( l~,h~$t~]:VIII Inlernaticmal ('onfereru:e on Endut:rinolugy. Abst #12-19-128.
10
IMMUNOMODUI,ATION 13Y ANTIC'ANCER AGENTS E. Mihich. (,ra{:e Cancer Drug Center. Roswell Park Menlorial Institute. 666 Elm Street, Bur|ale. NY, 14263.
Antiprolih:rative a n d cytotoxic antieant:er agents were initially found to inhibit {:ell-mediated and.'or hu, nmral ilnnmnn responses 11]. In rec:ent years it has become apparent that several uf tiles{," agellts nlav induce an a u g m e n t a t i u n (if certain i m n m n e responses u n d e r certain conditions anti may in fact he defined as having immunI~mudulating activity 12, 3]. While cyc:hlphosphamide inhibits prec:ursors uf T-suppressor cells I4. 51 other agents have diffe, renl selnl:tive a(:li(uls on tile i m m u n e system 12, 3. t5 81. In this report the i m m u n o m o dulating action of a d r i a m y c i n {ADM) is briefly dist:ussed as an example [9-11 ]. The differentiation of mac:rophages into phagocytic: 1!t. 121 or killer [13.14] {:ells is augnlented by ADM in C57H1,'6 mice. M a c r o p h a g e p r o d u c t i o n of such factors as 1I,-1 [14, 15]. TNF 116]. or PCJEz 191 is also stimulated hy the drug. Ill this strain ut mice, using PS1,5 as the allc.antigen. CTL responses ;','ere a u g m e n t e d by the drug given 5 days clr more before antigen in vivo or ex v i l e ¢)r early after antigen in vitro 19, 17. 181. This a u g m e n t a t i o n was associated with the inhibition of a plastic adherent T-regulatory cell and tile increased production of IL-2 [19,201. NK {:ell activity in PEC ',,,.'asaugmented anti in spleen inhibited by AI)M [14,151. Using syngnneic El,4 l y m p h n m a , tumor-associatect depression of l u m t m c i d a l C:TL. LAK cell, NK cell. and killer nlacrophages activities was found to be prevented ill mice given AI)M 5 days prior to t u m o r implantalion 121 ]; this effect was also seen w h e n an Al)M-resistant subline of EL4 was used 122], Therapeutic effects against this resistant suhline were noted w h e n AI)M was given in combination with IL-2 or It,-2 plus I,AK cells [23]. As i m n l u n o m o d u l a t i o n by ADM was also seen ill cancer patients given a single dose of drug 124] it may be pussibh: to develop clinical protocols exploiting this property of the drug toward therapeutic advantage. Tile studios with AI)M sunmlarized herein also support the (:uncept that antineoplastic drugs may be exploited as tcst~fcd tools ill basi¢: studies of illcnlun{lnlodulalion.
8
Abstracts
REFERENCES 1. Mihich E (19711: NCI Monograph 34:90-102. 2, E h r k e M [ , Mihich E(19841: Reticulnendothelial Svstem 8:309 347. :~. Ehrke MI. Mihich E (1985): Trends Pharmacol Sci e.:412 -t17. 4. Cowens el al. (1984): ] l m m u n n l 132:95-100. 5. Smith II, et al. (1987): Meth Find Exp ('lin Pharmacul 9:555-568. 6. Ryoyama K, et al. (1982): Int l l m n m n o p h a r m a c o 1 4 : 1 8 7 194. 7. Schlaefli E. et ill. (1983}: I m m u n o p h a r m a c o l o g y 6:187 122. 8. Ehrke MI, el al. (1988): Cancer Res 46:2798-2803. 9. Ehrke Nil. et al. (1982}: Immunol Re,.' 65:54 78. 10, Ehrke MI. Mihich E (1984): Clin Immunol Allergy 4:259 278 11 Mihich E. et al. [1985}: Biol Respons Cancer 3:71-94 12. Cohen SA, el al. (1982): l m m u n o p h a r m a c o l o g y 5:75 84. 13. Salazar D. Cohen SA [lg8"t): Cancer Res 44:2561 2566. 14. Mace K, el al. (19881: Cancer Res 48:130 136 15. Cohen SA. el al. (1983): Cancer l m m u n o l I m m u n o t h e r 15:188-193. 16. Macc~ K. et al. [1986): Leukocyte Biu 38:68. 17. Tnmazic V. el al. {1980): Cancer Res 4 0 : 2 7 4 8 - 2 7 5 5 18. Tomazic V. el ill, (1981): Cancer Res 41:3370 337(i. 19. Ehrke MI, et al, {19841: Cancer Res 4 4 : 2 4 9 7 - 2 5 0 4 211. Ehrke M], et al. 119881: Cancer Rc~s 4 6 : 5 4 - 6 0 21, Ehrke MI. et al. (19881: Pruc AACR 29:412. 22 M a c c u b b i n D, et al. {1987}: Proc Xth Intl Congress Pharmacol P1325, 23. Mihich E (1988}: Proc AACR 29:517-518. 24. Arinaga S, el ill (1986): Cancer Res 4{i:4213 4216.
11
ANTITUMOR IMMUNE RESPONSES FOLLOV¢ING CHEMOTHERAPY IN RATS. Masuo Hosokawa. Cancer Institute, Hokkaido University School of Medicine. Sapporo 060, Japan,
It is well k n o w n that c h e m o t h e r a p e u t i c drugs suppress the host i m n m n e responses. We have observed that therapeutic effects of c h e m o t h e r a p e u t i c drugs w o u l d be improved if the antitumur i m m u n e responses could tm restored or a u g m e n t e d following c h e m o t h e r a p y We examined a n t i t u m o r i m m u n e responses of tumur-bearing rats following c h e m o t h e r a p y in order to find out the correlation of therapeutic effects and the host i m m u n e responses against t u m o r cells. It ',','as found that the a n t i t u m o r i m m u n e responses were strongly suppressed in tumor-bearing rats after a singh; administration of c y c l o p h o s p h a m i d e (CY, 40 mg,'kg i.v.). Combined use of an i m m u n o s t i m u l a t o r y proteinb o u n d p o l y s a c c h a r i d e (PSK, 300 m g / k g / d a y i.p.) not only prevented the CY-induced i m m u n o s u p p r e s s i o n but also improved the therapeutic effects of CY. Our experiments also showed that antitunlor i m m u n e responses of tunlor-bearir~g rats wt;re a u g m e n t e d by an appropriately timed administration of bh:omycin (BLM). We have found the therapmltic effects of BI,M arc; d e p e n d e n t on the timing of its admirtistration after the t u m o r implantation. The therapeutic effects of BLM (5 m g ; k g / d a y i.p. for 5 days} was greater w h e n it was administered from 8 days after the t u m o r implantation (late BLM) than w h e n it was administered 1 day after the implantation (early BLMI. The a n t i t u m n r i m m u n e responses were examined by m e a s u r i n g tumor neutralizing activity and cytotoxic T l y m p h o c y t e (CTL] activity after the mixed l y m p h o c y t e t u m o r culture (MI,TC) of spleen cells. The responses were found to be a u g m e n t e d by late BI,M, but not by early BLM. These findings indicate that the therapeutic: effects of BLM arc; closely correlated with the a u g m e n t e d antitumor i m m u n e responses following the BLM treatment. The m e c h a n i s m s for the a u g m e n t e d a n t i t u m o r i m m u n e responses are s h o w n to be the elimination of suppressor T-lylnphncyte activity induced in the tumor-bearing rats and the activation of macrophagemediated cytotoxity by BLM. REFERENCES 1. A k i y a m a l. el al. (1977]: Cancer Res 37:3042-3045. 2. Morikawa K. et al. (1985): Cancer Res 45:684 688, 3. Morikawa K, et al. (1986): Cancer Res 46:1502-1506, 4. Xu Z-Y, et al. [1986): Cancer Immunol I m m u n o t h e r 23:46- 50. 5. Xu Z-Y, et al. Cancer Res [in press].