DSPG had a definite but relatively feeble immunosuppressive effect in rats undergoing heterotopic heart transplantation and in dogs after renal transplantation. The drug was toxic in both species, although less so in rats. In dogs, synergistic interactions with cyclosporine and steroids were not evident

Casavilla, A

Cemej, S

Ghalab, A

Kahn, D

Makowka, L

Mazzaferro, V

Murase, N

Nalesnik, M

Okuda, K

Pan, CE

Rhoe, BS

Starzl, TE

Taniguchi, K

Todo, S

Yang, M

English

PubMed

D-Scholarship@Pitt

Effect of 15-Deoxyspergualin on Experimental Organ Transplantation S. Todo, N. Murase, D. Kahn, C.E. Pan, K. Okuda, S. Cemej, A. Casavilla, V. Mazzaferro, A. Ghalab, B.S. Rhoe, M. Yang, K. Taniguchi, M. Nalesnik, L. Makowka, and T.E. Starzl 15-DEOXYSPERGUALIN (DSPG) is a new antitumor and immunosuppressive agent derived from the antibiotic spergualin. This agent was shown to prolong the graft survival of skin, heart, pancreas islet, kidney, and liver in the rodent. I-3 No observations have been made with large animals. In the present study, the effect of DSPG was first tested with rat heterotopic heart transplanta-tion (HTX) and then evaluated with canine kidney transplantation (KTX). MATERIALS AND METHODS Animals Lewis rats (RT I) purchased fwm the Harlan Spraque Dawley Company (Indianapolis) were used as recipients. ACI rats (RT 1') were purchased from the Simonsen Lab (Gilcoy, CAl and used as donors. Outbred beagle dogs were obtained from the Univer-sity of Pittsburgh farm and were used as both donors and recipients. Operative Procedures HTX was performed by the method of Ono and Lind-say.' The donor aorta and pulmonary artery were anasto-mosed to the recipient aorta and infrarenal inferior vena cava with standard microvascular techniques. KTX was performed by conventional intra-abdominal techniq)les, with which the renal artery was anastomosed to the recipient iliac artery end-to-end and the renal vein was anastomosed to the recipient iliac vein end-to-side. Bilat-eral native nephrectomy was performed after graft urete-ro-neocystostomy. Drug Administration DSPG was supplied as a powder from the Nippon Kayaku Company, Ltd, Tokyo. It was dissolved in saline, and was given intra peritoneally to the rat for 2 weeks and intravenousiy to the dog for 50 days starting immediately after the transplant operation. In experiments with drug combinations in dogs, cyclosporine (CyA) was given orally in the commercial oil carrier that is used clinically. Oral prednisone (Pred) was given to dogs as a 5-mg tablet. Experimental Groups Intraperitoneal doses tested in HTX were 0.0 mg/kg/d (control), 0.5 mg/kg/d, 1.0 mg/kg/d, 3.0 mg/kg/d, and 6.0 mg/kg/d. Treatment was for 14 days beginning just after the operation. Rejection was diagnosed by the cessation of heartbeat and was confirmed visually by laparotomy and histologic examination. The effect of intravenous DSPG alone and in combina-tion with oral CyA and Pred on KTX were examined in the following groups: I. Dose-effectiveness study Group I: (N ~ 6) DSPG (0.0 mg/kg/d) Group 2: (N ~ 6) DSPG (0.25 mg/kg/d) Group 3: (N ~ 6) DSPG (0.5 mg/kg/d) Group 4: eN ~ 6) DSPG (0.75 mg/kg/d) Group 5: (N ~ 6) DSPG (1.0 mg/kg/d) 2. Combination study Group 6: (N ~ 10) DSPG (0.5 mg/kg/d) + CyA (5 mg/kg/d) + Pred (5 mg/d) Group 7: (N ~ 6) DSPG (0.5 mg/kg/d) + CyA (5 mg/kg/d) Group 8: (N ~ 6) DSPG (0.5 mg/kg/d) + Pred (5 mg/d) Group 9: (N ~ 6) CyA (5 mg/kg/d) + Pred (5 mg/d) Group 10: (N ~ 6) CyA (5 mg/kg/d) Group II: (N ~ 6) Pred (5 mg/d) Because of emaciation of animals, the dose of DSPG in the combination experiments was reduced to 0.3 mg/ kg/d after 3 weeks and to 0.2 mg/kg/d after 6 weeks. Blood samples were collected every three mornings for the determination of kidney and liver functions. Complete postmortem examination of animals was performed. His-From the Department of Surgery. University Health Center of Pittsburgh. University of Pittsburgh. and the Veterans Administration Medical Center, Pittsburgh. Supported by research grants from the Veterans Administration and Project Grant No. AM 29961 from the National Institutes of Health. Bethesda. MD. Address reprint requests to S. Todo. MD. Department of Surgery. University Health Center of Pittsburgh, University of Pittsburgh. Falk Clinic. 3601 Fifth Ave. Pittsburgh. PA 15213. © 1988 by Grune & Stratton. Inc. 004/-1345/88/200 J -1087$03.0010 Transplantation Proceedings, Vol XX. No 1, Suppl 1 (February), 1988: pp 233-236 233 ---- -------------_ ..... _---_._-----234 TODO ET AL Table 1. Survival of Grafts by Intraperitonaallnjection of DSPG Dose Animals Died Median P Animals Died Group (mg/kg/d) No. of Rejection (Day) (Dayl kl of Infection 0.0 6 6,6,6,7,7 6 0/6 2 0.5 5 19,20,25,29,46 25 0.01 0/5 3 1.0 6 22,27,27,35,40 27 0.Q1 1/6 4 3.0 6 30,32 5 6.0 6 NOTE. DSPG was given from day 0 to day 13 (14 days total). tologic severity of graft rejection was determined blindly basing on subjective scales from 0 to + + +. Statistics Wilcoxon rank sum test and Student's t test were applied for the statistical analysis. RESULTS HTX The median graft survival of untreated rats was six days (Table 1). Intraperitoneal OSPG administration at doses of 0.5 mg/kg/d and 1.0 mg/kg/d provided significant prolonga-tion of graft survivaL Higher doses were lethaL Four of six rats in group 4 and all animals in group 5 died of bronchopneumonia even though the grafts were beating. Colony contamination with pathogens could not be shown by serologic and microbiologic study of nontransplanted rats from the same labora-tory environment. Thus, the deaths were attributed to over immunosuppression. 4/6 6/6 KTX Dose-effectiveness study. Mean survival was 13.3 ± 3.6 (SO) days in untreated control dogs, (Fig 1) while that of treated dogs (groups 2 to 5) was variable. Significant pro-longation of graft survival was obtained only with a dose of 0.75 mg/kg/d, group 4 (Fig 1), even though higher doses prevented creatinine (Cr) elevation (Fig 2) and even though histo-logic evidence of rejection was reduced at higher doses. The last Cr prior to animal death was 15.0 ± 4.6 (SO) mg/dL in group 1, 11.3 ± 3.8 in group 2, 5.4 ± 1.5 in group 3, 2.7 ± 2.8 in group 4; and 5.1 ± 3.4 in group 5. The prevention of Cr rise was significant in animals treated with 0.5 mg/kg/d or more of OSPG compared to groups 1 and 2. All ani-mals given 1.0 mg/kg/ d of OSPG died of lethal emacrrttion accompanied with severe diarrhea. Liver dysfunction was not observed in any group. Pulmonary congestion was the only pathologic abnormality in the extrarenal organs seemingly related to animal death. 100 • r-+-x-o 0-0 no treatment (N = 6) L!1L +-+ DSPG (O.25mg/kg/day) "tN=6) ,-. ff~ 0-0 DSPG (O.5mg/kg/day) (N=6) tfl. x-x DSPG (O.75mg/kg/dayl (N=6) ~ CD Tti o~ A-A DSPG (1.0mg/kg/day) (N=6) a; a: 50 til > > A-<>"""..-ct 0-0 x-x "- III I I ::> (/) A.d=c:> O--x--x·+ ~ I I 20 25 30 35 Fig 1. Survival of KTX 0 5 10 15 dogs treated with different Days after Transplantation doses of DSPG. 15-DEOXYSPERGUALIN IN ORGAN TRANSPLANTATION 235 GROUP I GROUP II GROUP III GROUP IV GROUP V (No Treatment) (DSPG (DSPG (DSPG (DSPG O.25mg/kg/day) O.5mg/kg/day) O.75mg/kg/day) t .Omg/kg/day) 25 20 ~ "0 -Ol E 15 Q) .= .= a; 10 Q) ~ () 5 o 20 40 0 20 40 0 20 40 0 20 40 0 20 40 Days after Transplantation Fig 2. Changes in serum creatinine of KTX dogs treated with different doses of DSPG. Drug combination. The results were com-pared with those in group 3 in which 0.5 mg/kg/d DSPG alone prolonged survival from 2 to about 3 weeks. The addition of 5 mg/kg/d CyA with (group 6) or without prednisone (group 7) augmented this effect, but not beyond what could be achieved with CyA alone (Group 10) or CyA plus predni-sone (group 9) (Fig 3). Thus, a clean-cut synergistic effect of DSPG with these other agents was not demonstrable. The best results were with cyclosporine, steroids, and DSPG. Elevation of Cr was well inhibited in this group of animals even though they died during the treatment. Emaciation and diarrhea were prominent in animals that were treated with DSPG for more than 3 weeks. Consequently, the dose of DSPG had to be reduced. Complete histopathologic anal-yses in animals subjected to the combination study has not yet been completed, but a pre-liminary observation is that rejection was absent or minimal in dogs under triple drug treatment. 100 0-0 DSPG + CyA + Pred (n = 10) x-x OSPG + CyA (n = 6) l--f-lt-xl-~ IL __ PSPG +Pred (n = 6) ---x-Jil-o <>-<> CyA + Pred (n = 6) Fig 3. Survival of KTX dogs treated with DSPG and other drugs; DSPG (0.5 mg/ kg/d). CyA (5 mg/kg/d). and Pred (5 mg/d). * 2 '" c:'" > > ... :::J en 50 o II rt A-A CyA (n = 6) _j n- 0 A-A Pred (n = 6) a_AX III llIIiiiiiiiiiiiijr-===m-0-A I ~= a--tk-----x-10 20 30 40 50 Days after Transplantation 236 DISCUSSION The present study is the first demonstration that DSPG inhibits the rejection of canine kidney homografts. However, the immuno-suppressive effect of DSPG alone was feeble and the toxicity was unacceptable. Doses of 0.75 mg/kg/d had a minor therapeutic affect but not enough to yield long animal survival. Doses higher than this caused the dogs to die of lethal emaciation. Toxicity was somewhat less in rats. How-ever, in contrast to the observation by oth-ersY most of our rats given higher doses of DSPG died from bronchopneumonia. No pathogen could be identified. The findings were different than those of Ochia et al3 who reported universal survival of WKA rats for more than 80 days, using the much higher dose of 10 mg/kg/ d intramuscularly. Sensi-tivity of rats to DSPG may differ among strains. Combination therapy is a potential alterna-tive method with which the toxicity of DSPG could be avoided if a reduced dose would work synergistically with other agents. These hopes TODO ET AL were not encouraged by actual experiments. Toxicity of DSPG persisted and the principal immunosuppression was from the CyA, which was an ingredient of the "cocktail." Thus, our results suggest that DSPG alone or in combi-nation probably will not be useful for clinical immunosu ppression. Before pushing ahead with more experi-ments, it may be wise to learn more of the mechanism of DSPG. DSPG has been said to inhibit the macrophage/phagocyte system instead of affecting lymphocytes.2 However, there are no well documented experiments to support this contention. Until such evidence is available, further attempts to combine DSPG with other agents are apt to be unrewarding. SUMMARY DSPG had a definite but relatively feeble immunosuppressive effect in rats undergoing heterotopic heart transplantation and in dogs after renal transplantation. The drug was toxic in both species, although less so in rats. In dogs, synergistic interactions with cyclo-sporine and steroids were not evident. REFERENCES I. Walter P, Thies J, Harbauer G, et al: Transplant Proc 18:1293, 1986 2. Dickneite G, Schorlemmer HU, Walter P, et al: Behring Inst Mitt 80:93, 1986 3. Ochiai T, Hori S, Nakajima K, et al: Antibiotics 40:249,1987 4. Ono K, Lindsay L: J Thorae Cardiovasc Surg 7,:225, 1969 

Effect of 15-deoxyspergualin on experimental organ transplantation

S. Todo

N. Murase

D. Kahn

C.E. Pan

K. Okuda

S. Cemej

A. Casavilla

V. Mazzaferro

A. Ghalab

B.S. Rhoe

M. Yang

K. Taniguchi

M. Nalesnik

L. Makowka

T.E. Starzl

AIR Universita degli studi di Milano

Effect of 15-Deoxyspergualin on Experimental Organ
Transplantation
S. Todo, N. Murase, D. Kahn, C.E. Pan, K. Okuda, S. Cemej, A. Casavilla, V. Mazzaferro, A.
Ghalab, B.S. Rhoe, M. Yang, K. Taniguchi, M. Nalesnik, L. Makowka, and T.E. Starzl
Department of Surgery, University Health Center of Pittsburgh, University of Pittsburgh, and the
Veterans Administration Medical Center, Pittsburgh.
15-Deoxyspergualin (DSPG) is a new antitumor and immunosuppressive agent derived from
the antibiotic spergualin. This agent was shown to prolong the graft survival of skin, heart,
pancreas islet, kidney, and liver in the rodent. 1–3 No observations have been made with large
animals. In the present study, the effect of DSPG was first tested with rat heterotopic heart
transplantation (HTX) and then evaluated with canine kidney transplantation (KTX).
MATERIALS AND METHODS
Animals
Lewis rats (RT 1) purchased from the Harlan Spraque Dawley Company (Indianapolis) were
used as recipients. ACI rats (RT 1a) were purchased from the Simonsen Lab (Gilcoy, CA) and
used as donors.
Outbred beagle dogs were obtained from the University of Pittsburgh farm and were used as
both donors and recipients.
Operative Procedures
HTX was performed by the method of Ono and Lindsay.4 The donor aorta and pulmonary
artery were anastomosed to the recipient aorta and infrarenal inferior vena cava with standard
microvascular techniques. KTX was performed by conventional intra-abdominal techniques,
with which the renal artery was anastomosed to the recipient iliac artery end-to-end and the
renal vein was anastomosed to the recipient iliac vein end-to-side. Bilateral native nephrectomy
was performed after graft uretero-neocystostomy.
Drug Administration
DSPG was supplied as a powder from the Nippon Kayaku Company, Ltd, Tokyo. It was
dissolved in saline, and was given intraperitoneally to the rat for 2 weeks and intravenously to
the dog for 50 days starting immediately after the transplant operation. In experiments with
drug combinations in dogs, cyclosporine (CyA) was given orally in the commercial oil carrier
that is used clinically. Oral prednisone (Pred) was given to dogs as a 5-mg tablet.
Experimental Groups
Intraperitoneal doses tested in HTX were 0.0 mg/kg/d (control), 0.5 mg/kg/d, 1.0 mg/kg/d, 3.0
mg/kg/d, and 6.0 mg/kg/d. Treatment was for 14 days beginning just after the operation.
© 1988 by Grune & Stratton, Inc.
Address reprint requests to S. Todo, MD, Department of Surgery, University Health Center of Pittsburgh, University of Pittsburgh, Falk
Clinic, 3601 Fifth Ave, Pittsburgh, PA 15213.
NIH Public Access
Author Manuscript
Transplant Proc. Author manuscript; available in PMC 2010 October 14.
Published in final edited form as:
Transplant Proc. 1988 February ; 20(1 Suppl 1): 233–236.
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Rejection was diagnosed by the cessation of heartbeat and was confirmed visually by
laparotomy and histologic examination.
The effect of intravenous DSPG alone and in combination with oral CyA and Pred on KTX
were examined in the following groups:
1. Dose-effectiveness study
Group 1: (N = 6) DSPG (0.0 mg/kg/d)
Group 2: (N = 6) DSPG (0.25 mg/kg/d)
Group 3: (N = 6) DSPG (0.5 mg/kg/d)
Group 4: (N = 6) DSPG (0.75 mg/kg/d)
Group 5: (N = 6) DSPG (1.0 mg/kg/d)
2. Combination study
Group 6: (N = 10) DSPG (0.5 mg/kg/d) + CyA (5 mg/kg/d) + Pred (5 mg/d)
Group 7: (N = 6) DSPG (0.5 mg/kg/d) + CyA (5 mg/kg/d)
Group 8: (N = 6) DSPG (0.5 mg/kg/d) + Pred (5 mg/d)
Group 9: (N = 6) CyA (5 mg/kg/d) + Pred (5 mg/d)
Group 10: (N = 6) CyA (5 mg/kg/d)
Group 11: (N = 6) Pred (5 mg/d)
Because of emaciation of animals, the dose of DSPG in the combination experiments was
reduced to 0.3 mg/kg/d after 3 weeks and to 0.2 mg/kg/d after 6 weeks. Blood samples were
collected every three mornings for the determination of kidney and liver functions. Complete
postmortem examination of animals was performed. Histologic severity of graft rejection was
determined blindly basing on subjective scales from 0 to + + +.
Statistics
Wilcoxon rank sum test and Student’s t test were applied for the statistical analysis.
RESULTS
HTX
The median graft survival of untreated rats was six days (Table 1). Intraperitoneal DSPG
administration at doses of 0.5 mg/kg/d and 1.0 mg/kg/d provided significant prolongation of
graft survival. Higher doses were lethal. Four of six rats in group 4 and all animals in group 5
died of bronchopneumonia even though the grafts were beating. Colony contamination with
pathogens could not be shown by serologic and microbiologic study of nontransplanted rats
from the same laboratory environment. Thus, the deaths were attributed to over
immunosuppression.
KTX
Dose-effectiveness study—Mean survival was 13.3 ± 3.6 (SD) days in untreated control
dogs, (Fig 1) while that of treated dogs (groups 2 to 5) was variable. Significant prolongation
of graft survival was obtained only with a dose of 0.75 mg/kg/d, group 4 (Fig 1), even though
higher doses prevented creatinine (Cr) elevation (Fig 2) and even though histologic evidence
of rejection was reduced at higher doses. The last Cr prior to animal death was 15.0 ± 4.6 (SD)
mg/dL in group 1, 11.3 ± 3.8 in group 2, 5.4 ± 1.5 in group 3, 2.7 ± 2.8 in group 4; and 5.1 ±
Todo et al. Page 2
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3.4 in group 5. The prevention of Cr rise was significant in animals treated with 0.5 mg/kg/d
or more of DSPG compared to groups 1 and 2. All animals given 1.0 mg/kg/d of DSPG died
of lethal emaciation accompanied with severe diarrhea. Liver dysfunction was not observed in
any group. Pulmonary congestion was the only pathologic abnormality in the extrarenal organs
seemingly related to animal death.
Drug combination—The results were compared with those in group 3 in which 0.5 mg/kg/
d DSPG alone prolonged survival from 2 to about 3 weeks. The addition of 5 mg/kg/d CyA
with (group 6) or without prednisone (group 7) augmented this effect, but not beyond what
could be achieved with CyA alone (Group 10) or CyA plus prednisone (group 9) (Fig 3). Thus,
a clean-cut synergistic effect of DSPG with these other agents was not demonstrable.
The best results were with cyclosporine, steroids, and DSPG. Elevation of Cr was well inhibited
in this group of animals even though they died during the treatment. Emaciation and diarrhea
were prominent in animals that were treated with DSPG for more than 3 weeks. Consequently,
the dose of DSPG had to be reduced. Complete histopathologic analyses in animals subjected
to the combination study has not yet been completed, but a preliminary observation is that
rejection was absent or minimal in dogs under triple drug treatment.
DISCUSSION
The present study is the first demonstration that DSPG inhibits the rejection of canine kidney
homografts. However, the immunosuppressive effect of DSPG alone was feeble and the
toxicity was unacceptable. Doses of 0.75 mg/kg/d had a minor therapeutic affect but not enough
to yield long animal survival. Doses higher than this caused the dogs to die of lethal emaciation.
Toxicity was somewhat less in rats. However, in contrast to the observation by others,2,3 most
of our rats given higher doses of DSPG died from bronchopneumonia. No pathogen could be
identified. The findings were different than those of Ochia et al3 who reported universal
survival of WKA rats for more than 80 days, using the much higher dose of 10 mg/kg/d
intramuscularly. Sensitivity of rats to DSPG may differ among strains.
Combination therapy is a potential alternative method with which the toxicity of DSPG could
be avoided if a reduced dose would work synergistically with other agents. These hopes were
not encouraged by actual experiments. Toxicity of DSPG persisted and the principal
immunosuppression was from the CyA, which was an ingredient of the “cocktail.” Thus, our
results suggest that DSPG alone or in combination probably will not be useful for clinical
immunosuppression.
Before pushing ahead with more experiments, it may be wise to learn more of the mechanism
of DSPG. DSPG has been said to inhibit the macrophage/phagocyte system instead of affecting
lymphocytes.2 However, there are no well documented experiments to support this contention.
Until such evidence is available, further attempts to combine DSPG with other agents are apt
to be unrewarding.
SUMMARY
DSPG had a definite but relatively feeble immunosuppressive effect in rats undergoing
heterotopic heart transplantation and in dogs after renal transplantation. The drug was toxic in
both species, although less so in rats. In dogs, synergistic interactions with cyclosporine and
steroids were not evident.
Todo et al. Page 3
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Acknowledgments
Supported by research grants from the Veterans Administration and Project Grant No. AM 29961 from the National
Institutes of Health, Bethesda, MD.
REFERENCES
1. Walter P, Thies J, Harbauer G, et al. Transplant Proc 1986;18:1293.
2. Dickneite G, Schorlemmer HU, Walter P, et al. Behring Inst Mitt 1986;80:93. [PubMed: 3092796]
3. Ochiai T, Hori S, Nakajima K, et al. Antibiotics 1987;40:249.
4. Ono K, Lindsay L. J Thorac Cardiovasc Surg 1969;7:225. [PubMed: 4884735]
Todo et al. Page 4
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Fig 1.
Survival of KTX dogs treated with different doses of DSPG.
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Fig 2.
Changes in serum creatinine of KTX dogs treated with different doses of DSPG.
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Fig 3.
Survival of KTX dogs treated with DSPG and other drugs; DSPG (0.5 mg/kg/d), CyA (5 mg/
kg/d), and Pred (5 mg/d).
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Todo et al. Page 8
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Transplant Proc. Author manuscript; available in PMC 2010 October 14.


Cemaj, S

Name not available

Effect of 15-Deoxyspergualin on experimental organ transplantation

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Effect of 15-deoxyspergualin on experimental organ transplantation

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