(CANCER RESEARCH 28, 2032-2038, October 1968]

inoculation of a tumor mince into the pulmonary vasculatureof adult rhesus monkeys receiving cortisone and a progestationalagent. These animals were treated with cortisone to suppressthem immunologically and a progestational agent to partiallymimic the hormonal status of pregnancy, the condition in whichthis malignancy arises. Growth in the lungs would permit theresponse of the tumor to be followed by X-rays as well asgonadotropin determinations. Also, lungs are the most commonsite of metastases in patients with metastatic choriocarcinoma(16, 19), so it was thought that this would be the best analogyto the growth pattern in the human malignancy. When thiseffort proved unsuccessful, similar intravascular inoculation wastried in another group of adult rhesus monkeys at the time ofthymectomy, followed by the daily administration of rabbitantirhesus lymphocyte serum (ALS) . Treatment with heterologous ALS has been shown by others to be effective in prolonging allografts in mice (13, 14), rats (20), and dogs (18)and is currently being evaluated as a form of immunosuppressive therapy in human renal allografts (18) . The thymectomywas carried out in an effort to prolong the effectiveness of theALS treatment (15) . The preparations of ALS used in thisstudy have been effective in prolonging skin allograft survivalin rhesus monkeys (R. C. Davis and J. L. Lewis, Jr., unpublished data).

Successful transplantation of human choriocarcinoma inmonkeys occurred only when it was transplanted to an immunologically privileged site—the brain. This was done in adultrhesus (Macaca mulatta) and newborn cynomolgus (Macacali-us) monkeys. Tumor growth in the adults was progressiveand predictable enough to recommend this system as a chemotherapy model. It can also serve as a useful model for studyingthe effect of tumor growth in a primate brain. Because growthof the tumor was not as successful in the brain of newbornsas in adults, and since the methods of tumor preparation inthese two groups were different, the effect of the method ofpreparation on tumor growth in the hamster cheek pouch wasstudied.

MATERIALS AND METHODS

Human Choriocarcinoma

Three strains (WO, GR, and RE) of the Erwin-Turner choriocarcinoma previously described by Hertz (9) were used inthis study. These strains have been serially transplanted inthe cheek pouch of golden Syrian hamsters (Mesocricetusauratus) and no longer require cortisone, although this wasused in early transplant generations.

At the time of this study, these strains were in the following

1 This work was supported in part under National Cancer In

stitute Contract No. PH 43-66—84 to Hazieton Laboratories, Inc.,Falls Church, Virginia.

2 Present address : Gynecology Service, Memorial Hospital for

Cancer and Allied Diseases, New York, New York 10021.3 Present address : National Institute of Child Health and Hu

man Development, Bethesda, Maryland.4 Present address : Department of Surgery, Boston University

School of Medicine, Boston, Massachusetts.Received December 26, 1967; accepted June 13, 1968.

2032 CANCER RESEARCH VOL.28

Heterotranspiantation of Human Choriocarcinoma in Monkeys'

John 1.Lewis,Jr.,2Willis E.Brown,Jr., RoyHertz,3Robert C. Davis,4and Robert H. Johnson,Jr.Surgery and Endocrinology Branches, National Cancer Institute, Bethesda, Maryland 50014

SUMMARY

Human choriocarcinoma has been transplanted to the pulmonary vasculature of seven adult rhesus monkeys and to thebrains of ten adult rhesus and four newborn cynomolgusmonkeys.

Progressive tumor growth was noted in all of the adults receiving solid implants of tumor in the cerebral cortex and halfof the newborns who had a mince of choriocarcinoma injectedinto the cortex through a needle placed through the coronalsuture. Tumor was transplanted from these lesions back intothe cheek pouch of hamsters as a test of viability. Death ofthe monkeys bearing transplants was preceded by localizingneurologic signs of expanding intracranial lesions. The administration of heterologous antilymphocyte sera did not affect thepattern of tumor growth nor the host's cellular reaction aroundthe tumor.

No growth was seen when tumor was injected into the inflowtract of the right side of the heart and then flushed into thepulmonary vasculature. Three monkeys treated this way received cortisone and a progestational agent. The other fourunderwent thymectomy and then received heterologous antilymphocyte sera, a form of treatment which had been shownto be effective in suppressing a homograft response in thisspecies.

INTRODUCTION

Human gestational choriocarcinoma has previously been suecessfully transplanted in cortisone-treated and untreated hamsters, in cortisonized-irradiated rats (7, 9) , and in the brain ofuntreated rabbits (H. S. N. Greene, personal communication).Several strains of this trophoblastic malignancy have been suecessfully grown by Hertz and can be carried through serialtransplants in the hamster cheek pouch without cortisone (someneeded no cortisone from the start) . This report is of our effortsto transplant this human neoplasm in monkeys.

Our first efforts were to attain growth by the intravascular

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MonkeySimultaneousgrowth inhamstersEvaluation

of tumor- growth inmonkeyExamination

atwhich no Time of

tumor was examinationfound(weeks)Series

I-AJ-138Not evaluatedThoracotomy 6

Thoracotomy9J-83Not

evaluatedThoracotomy3J-90Not

evaluatedAutopsy3Series

I-B16529 of 11Thoracotomy@ 5.

Thoracotomy 9Autopsy15T1168

of 9Thoracotomy 4Autopsy13148311

of 11Thoracotomy 4.Autopsy13R146810

of 16Autopsy 35

Choriocarcinoma Heterotransplantation

generations : RE, 56th and 57th ; GR, 25th ; and WO, 121stand 322nd through 326th. Fresh tumor specimens were obtainedfrom the cheek pouch for transplanting into monkeys. Forintravascular injections and inoculations into the cerebral cortex of the newborn, tumor was minced with a knife until itwould pass through a 20-gauge needle. It was then suspendedin cold isotonic saline and injected within one hour of removalfrom the hamster. Tumor implants in the cortex of adult rhesusmonkeys were done with solid pieces of tumor measuring approximately I .5 mm in each dimension. In all but the first threemonkeys (Series I-A, Table 1), the tumor used for these studieshad a simultaneous test of viability by placing pieces of thetumor into the cheek pouch of untreated hamsters. This testwas also used to test the viability of tumors which grew inmonkeys.

The histologic pattern of these tumors has remained remarkably constant throughout their transplantation generations. Thetumor is composed of pleomorphic, anaplastic cells of bothcytotrophoblastic and syncytiotrophoblastic types. They invariably are associated with hemorrhage and necrosis. Varying degrees of cellular reaction surround the tumor. Grossly theyhave a reddish to purplish-black color. A piece of tumor implanted in a hamster cheek pouch is considered to have grownwhen it assumes a reddish-purple to blue-black color in one totwo weeks and increases in volume 20—100-fold.

Monkeys

Commercially obtained adult rhesus monkeys of both sexeswere used. They were housed separately and kept on routinefood, water ad libitum, and fresh fruit daily. Animals whichreceived tumor intravascularly had at least one chest X-raypostoperatively. Animals with tumor transplanted into the brainwere observed for neurologic signs daily. The cynomolgus

monkeys were born in a closed primate colony and cared forin a newborn primate nursery.

Antilymphocyte Sera

The antilymphocyte sera used in Series I-B and Il-B wereobtained by injecting cells from adult rhesus monkey lymphnodes or thymus glands into rabbits according to an immunization procedure described by Gray (5) . The blood from theserabbitts was allowed to stand at 4°C for 24 hours, the serumwas separated, heated at 55°C for one hour, and then storedat 4°C. These sera had lymphoagglutimn titers of 1 :256 to1 : 1024 when tested with rhesus monkey lymphocytes but lowertiters when tested with cells from cynomolgus monkey lymphnodes. The ALS used in Series Il-A was similarly prepared,but the animal used for generating this antiserum was a burro.The rabbit ALS had been shown capable of producing lymphopenia and prolonging skin allografta in rhesus monkeys inthis laboratory and was thus thought to represent an effectiveimmunosuppressive treatment. Only the ability of the burroALS to agglutinate lymphocytes was tested. All ALS was administered subcutaneously, 3 ml daily to adults and 0.5 ml dailyto newborns.

EXPERIMENTAL PLAN

Tumor Implantation in Pulmonary Vaseulature

Series I-A. In this group of three adult female rhesus monkeys, a mince of human choriocarcinoma was injected througha polyethylene catheter which was threaded from the inferior

vena cava to a position near the right atrium. A volume oftumor adequate to transplant 10 hamsters was injected into

each animal and then flushed slowly through the catheter with

Table1

Inoculation of mince of human choriocarcinoma into pulmonary vasculature of adult rhesusmonkeys.

OCTOBER 1968 2033

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MonkeySimultaneousgrowth inhamstersTreatmentOutcomeTumor

found inbrainHistologyGrowthin

hamsters10

of 12NoneProgressive CNS signs. Sacrificed at 22 days.Viable

choriocarcinoma3 of7371-W11

of 12ALSCNS signs. Died at 21 days.Viable choriocarcinoma3 of6374.-W5of 10ALSCNS signs. Died at 19 days.Rim o viable chorio

carcinoma5of6398-W9

of 16NoneCNS signs. Moribund whensacrificed at 19 days.Viable

choriocarcinoma5 of8937-W6

of 6NoneCNS signs. Died at 23 days.Islands of viablechoriocarcinoma4

of4939-WSame

donor as 937-WALSCNS signs. Died at 21 days.Rim of viable choriocarcinoma4

of5936-W22

of 23NoneCNS signs. Died at 17 days.Viable choriocarcinoma6 of11941-WSamedonor as 936-WALSCNS signs. Died at 16 days.Viable choriocarcinoma1 of6938-W9

of 11ALSCNS signs. Died at 21 days.A few viable choriocarcinoma cells5

of7940-WSame

donor as 938-WNoneCNS signs. Moribund whensacrificed at 21 days.A

few degeneratingchoriocarcinoma cells2

of8Corticalimplantation

of humanchoriocarcinoma in adult rhesus monkeys. ALS,antilymphocyte serum ; CNS,centralnervous

J. L. Lewis, Jr., W. E. Brown, Jr., R. Hertz, R. C. Davis, and R. H. Johnson, Jr.

examined at autopsy, any tissue in the brain which appeared tobe viable choriocarcinoma was implanted in the cheek pouchof hamsters as well as submitted for histologic study. In addition, a complete autopsy was performed on each of these animals to determine if there were metastases.

All of the monkeys in this series had cerebral angiographicstudies at the time they were exhibiting neurologic symptomssuggestive of an expanding intracranial lesion. Five of themalso had radioisotopic brain scans. The results of these studieswill be reported separately.

Series fl-B. Efforts to grow human choriocarcinoma werealso carried out simultaneously in newborn cynomolgus monkeys. Four animals were injected within 24 hours of birth witha mince of WO strain choriocarcinoma. After a surgical prepof the scalp, a 20-gauge needle was passed through the rightcoronal suture line approximately 2 cm to the right of midline and to a depth of 7—10mm. As noted in Table 3, two ofthem received 0.5 ml of rabbit ALS s.c. daily. The animalswere observed daily for neurologic signs. Two were sacrificedwhen asymptomatic at 40 and 49 days after implantation. Tumor which appeared to be viable at the time of autopsy wastransplanted into hamsters. A complete autopsy was alsoperformed.

Effects of Preparation of Tumor Implants on Growth ofChoriocarcinoma in the Hamster Cheek Pouch

A single large transplant of human choriocarcinoma growingin a hamster cheek pouch was processed in two ways for transplantation into the cheek pouch of 20 hamsters. One third ofthe tumor was divided into 10 implants approximately 1.5 mmin each dimension (the same size used for the cortical implantsin the adult monkeys) . The rest of the tumor was minced witha scalpel and suspended in approximately 2 ml of saline (apreparation similar to that used in the other monkey studies).This tumor suspension was then injected through a 20-gauge

Table2

10 ml of sterile saline. All three animals received 25 mg cortisone acetate s.c. daily and either 20 mg of 19-norethisteroneor 40 mg of medroxyprogesterone p.o. daily. The animals wereevalulated by chest X-rays and histologic examination of tissueobtained at the time of exploratory thoracotomy or autopsy,as noted in Table 1. The viability of the tumor injected inthese animals was not tested by simultaneous implantation ofpieces of the tumor in the cheek pouch hamsters, but the tumorappeared the same as that chosen for propagation.

Series I-B. Six adult rhesus monkeys of both sexes were usedin this study. Surgical thymectomy was carried out througha midline, sternum-splitting approach. A mince of WO strainchoriocarcinoma was prepared as in Series I-A and injectedinto the right atrium through a 20-gauge needle. Each monkeyreceived 3 ml of rabbit ALS s.c. daily for 25—28days. Twoanimals died within three days of surgery, presumably due tooperative complications, serum treatment, or a combination ofthese factors ; they are not included in Table 1. Tumor growthwas evaluated at the time of thoracotomy or autopsy. Viabilityof the tumor used for inoculation is indicated by the numberof tumors that developed in the simultaneously implantedhamsters.

Tumor Implantation in the Brain

Series fl-A. Implants of WO strain choriocarcinoma measuring 1.5 mm in each dimension were placed in the cerebral cortexof 10 adult rhesus monkeys of both sexes, as seen in Table 2.Under sterile conditions an incision was made in the left frontoparietal area and the temporalis muscle was divided and retracted. A craniectomy measuring 1—1.5 cm in diameter wascreated. The dura were incised and reflected. Four pieces of tumor were implanted in the cortex through incisions approximately 2 mm deep and approximately 1 cm apart. Five of themonkeys received 3 ml of burro ALS s.c. daily for 16—18days.Each animal was evaluated daily for neurologic signs. When

system.

CANCER RESEARCH VOL.282034

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MonkeySimultaneousgrowth inhamstersTreatmentOutcomeTumor

found inbrainHistologyGrowthin

hamsters524-G9

of 21ALSProgressive CNS signs. Sacrificedwhen moribund at 21 days.Viable

choriocarcinoma10 of13526-G3

of 7NoneAutopsied at 7 weeks. Asymptomatic.AbscessNot

done529-G2

of 5ALSSeizure at 12 days. Asymptomaticat autopsy, Day 40.Degenerating

trophoblastic cellsin scar tissueNot

done537-G8

of 9NoneNeurologic signs. Sacrificed atDay 12.Viable

choriocarcinoma5 of6Corticalimplantation

of amince humanchoriocarcinoma in newborn cynomolgusmonkeys. ALS, antilymphocyte serum ; CNS,

Choriocarcinoma Heterotranspkzntation

Table 3

central nervous system.

needle into the cheek pouch of 10 hamsters, each receiving0.2 ml of the tumor suspension. The hamsters were anesthetizedat weekly intervals and the cheek pouch everted to evaluatethe growth of the implants. Growth was indicated by an enlargement of the implant to an average diameter of at least4—5mm and the change in color to a reddish-purple to blueblack color.

RESULTS

Tumor Implantation in Pulmonary Vaseulature

There was no evidence of persistence or growth of the humanchoriocarcinoma injected as a mince into the pulmonary vasculature of the seven adult monkeys in Series I-A and I-B. Simultaneous growth of the donor tumors used in Series I-B in 37of 47 hamsters clearly indicates tumor viability. A thoroughsearch for viable tumor was made by serial sections of the lungbiopsies in Series I-A and by complete autopsy of the animalsin Series I-B. Total white blood cell counts and differentialwhite blood counts of the peripheral blood in the animals receiving ALS showed a lymphopenia which was maximal in thefirst week of treatment.

Tumor Implantation in Brain

Series H-A. Evidence of tumor growth was found in all tenof the adult rhesus monkeys which had cortical implants ofhuman choriocarcinoma. The tumor grew progressively, produced localizing neurologic signs, and killed 8 of the 10 animalsin 16 to 21 days. Another animal was autopsied when moribundat 19 days, and the last animal was sacrificed 22 days afterimplantation. At that time this monkey had a right hemiparesis but was not moribund.

A complete autopsy was carried out in each of these monkeys.Tumor found growing at the site of tumor implantation wasthen studied in hamsters. Grossly, large tumor masses werepresent in each brain. Microscopically, the specimens in 8 ofthe 10 animals showed the typical pattern of anaplastic syncytial and cytotrophoblastic cells with varying degrees of hemorrhage, necrosis, and cellular infiltrate from the host. Thetumor in the other two animals showed either a small numberof viable trophoblastic cells or a mass of degenerating cells,compatible with but not diagnostic. of trophoblastic origin. How

ever, when tumor from each of these 10 monkeys was transplanted back into hamsters, there was growth of choriocarcinoma in at least one of the hamsters receiving each tumor.The nature of these growths was confirmed histologically. Bioassay of the serum from one of the monkeys bearing a tumorimplant gave a positive result for chorionic gonadotropin whenassayed by a modification of the method of Klinefelter (11).Fig. 1 shows tumor growing in the brain of one of the adultrhesus monkeys. Some of these tumors showed a heavy infiltrate of mononuclear white cells surrounding the tumor growing in the brain. However, no correlation was found with thisobservation and the administration of ALS. No evidence ofmetastases was found in any animal.

Series Il-B. The outcome of intracerebral inoculation ofchoriocarcinoma into newborn cynomolgus monkeys is shownin Table 3. Progressive growth, noted both grossly and histologically, was found in two animals. One was sacrificed whenmoribund at 21 days and the other when symptomatic at 12days. Fig. 2 shows a series of coronal sections of the brain ofone of these animals. The histology of these growths was thesame as that found when choriocarcinoma grows either in adultmonkey brain or in the hamster cheek pouch. A third animalhad a left-sided seizure 12 days after inoculation but thenbecame asymptomatic. When autopsied at 40 days, a few degenerating trophoblastic cells were associated with a fresharachnoid scar. The fourth animal revealed no signs of tumor growth but when autopsied at 49 days was found to havean asymptomatic brain abscess. When pieces of the two histologically viable tumors were transplanted back into hamsters,each showed growth.

Effect of Preparation of Tumor Iniplants on Growth ofChoriocarcinoma in the Hamster Cheek Pouch

The method of preparation of tumor for implantation or inoculation affected its growth in the hamster cheek @pouchsystern. Whereas tumors grew in 8 of 10 hamsters receiving solidimplants (as used in adult monkey brains), growth was foundin only 2 of 10 hamsters receiving the same tumor as a mince(as used in newborn monkey brains) . This difference is statistically significant (chi square, P < 0.05) and indicates thatmincing the tumor decreases its viability. Efforts •to obtainsingle cell suspensions of this tumor by trypsinization decreasedtumor viability to an even greater degree.

OCTOBER 1968 2035

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J. L. Lewis, Jr., W. E. Brown, Jr., R. Hertz, R. C. Davis, and R. H. Johnion, Jr.

DISCUSSION

The observation that a human malignancy will grow progressively in the brain of a monkey has not, to the author'sknowledge, been previously reported. Efforts in monkeys totransplant HeLa cells and human epidermoid cancer cells, previously grown in tissue culture or heterologous hosts, have notbeen successful ( 12) . On the other hand, there have been reports of successful growth of human cancers in the brains oflower species (2, 6) . Also, primate tumors, both virus ( 1) andcarcinogen-induced ( 10) , have been successfully transplantedto the brain of primates. One possible explanation for the suecessful growth of human choriocarcinoma in the monkey brainis that during its more than 300 generations in the hamsterthe tumor has lost its human antigens and therefore does notelicit a xenogeneic immune response. Against this hypothesisis the observation that prior immunization of hamsters withhuman 7-globulin (9) will prevent the growth of subsequentlytransplanted human choriocarcinoma. Presumably, success inthis site is due in part to the well-reported observation thatthe brain is a relatively privileged site for transplantation (17).

It was initially surprising that human choriocarcinoma failedto grow as well in the brain of newborn cynomolgus monkeysas in adult rhesus monkeys. However, two observations discussed earlier help explain this. The fact that the tumors usedin the newborns did not grow in as high a percentage whentested for viability in hamsters favors growth in the adults.Also, the finding that mincing the tumor decreases its viabilitywould decrease the likelihood of growth when compared to thatof solid implants in the adult brains.

Failure of growth of the tumor mince flushed into the pulmonary vasculature may be due to any of several causes. The factthat there was growth in 38 of 47 implantations in hamstercontrols planted with the same tumors used in Series I-B mdicates that the tumor was viable. We have no direct evidencein monkeys that the tumors can survive vascular transport,but it would seem reasonable from Ehrmann's work with thesame tumor in hamsters (3) . As noted earlier, mincing of thetumor to a size which can pass through a needle apparentlyhas a damaging effect on its viability, and this may have beenpartially .responsible.@

Studies of transplants in newborns were discontinued whenit was evident that there was excellent growth in each of theadult monkeys. The adults have other obvious advantageswhich recommend them in preference to the newborns. Theyare easier to obtain commercially than riewborns. They@ areeasier to care for after transplantation: Their metabolism ofchemotherapeutic agents is more predictable. The transplantation of tumor can be done at a time when excellent tumoris available from propagation in the hamster cheek pouch ratherthan having to use the best tumor available at the time thata baby monkey is born. T@ie adults are also@ better able towithstand the , stress of the diagnostic studies employed, suchas angiography, brain scan, and repeated venepunctures.

The use of ALS to suppress the immune response seemedlike a reasonable effort at the onset of these studies. However,it proved to be@ no demonstrable advantage. In the animalswith successful transplantation to the brain there was no differ

ence in the pattern of growth or the cellular reaction to the tumor related to whether the animals received ALS. On theother hand, if an immune response was responsible for thefailure of the tumor to grow when inoculated into the pulmonary vasculature, this treatment was not able to overcome it.

Although metastases to the brain of human choriocarcinomais not as common a clinical problem as pulmonary metastases,it is still a common problem. Failure of central nervous systemmetastases to respond to chemotherapy has been reported asthe most prevalent cause of death in patients undergoing chemotherapy (19) . The fact that human choriocarcinoma grows progressively when transplanted to the brain of an animal specieswhich handles chemotherapeutic drugs similarly to man makesit a potentially useful model for evaluating new drugs and otherforms of therapy of intracranial metastases.

Predictable growth of human choriocarcinoma in a primatebrain is a potentially useful chemotherapy model to test newdrug therapy. The observation that chemotherapy studies inprimates give a better prediction of human drug toxicity thando similar studies in hamsters (4) makes this tumor model inprimates a better system in which to measure tumor-to-hosttoxicity ratios than the hamster cheek pouch system currentlyin use (8).

ACKNOWLEDGMENTS

We thank Dr. Margaret Kelly, Laboratory of Chemical Pharmacology, National Cancer Institute, Bethesda, Maryland, for makingthe cynomolgus monkeys available to this study.

REFERENCES

1. Ausman, J. I., and Owens, G. The Production of a VirusInduced Tumor in the Central Nervous System of Monkeys.

J. Neurosurg., 21: 660-666, 1964.2. Chesterman, F. C. Intracranial Heterotranspiantation of Hu

man Tumors. Brit. J. Cancer, 9: 51-61, 1955.3. Ehrmann, R. L., and Gliserman, L. E. Choriocarcinoma:

Growth Patterns in Hamster Tissues. Nature, 502: 404-406,1964.

4. Freireich, E. J., Gehan, E. A., Rail, D. P., Schmidt, L. H., andSkipper, H. E. Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey, andMan. Cancer Chemotherapy Rept., 50: 219—244,1966.

5. Gray, J. G., Monaco, A. P., Wood, M. L., and Russell, P. 5.Studies on Heterologous Anti-lymphocyte Serum in Mice. I. InVitro and In Vivo Properties. J. Immunol., 96: 217—228,1966.

6. Greene, H. S. N. The Transplantation of Tumors to the Brainsof Heterologous Species. Cancer Res., 11 : 529—534,1951.

7.. Hertz, R. Choriocarcinoma of Women Maintained in SerialPassage in Hamster and Rat. Proc. Soc. Exptl. Biol. Med., 105:77—81,1959.

8. Hertz, R: Suppression of Human Choriocarcinoma Maintainedin the Hamster Cheek Pouch by Extracts and Alkaloids ofVinca Rosea. Proc. Soc. Exptl. Biol. Med., 105: 281—282,1960.

9. Hertz, R. Serial Passage of Choriocarcinoma of Women in the@ . Hamster Cheek Pouch. In: J. F. Holland and M. M. Hreshchy

. shyn (eds.), Choriocarcinoma, UICC Monograph Series, Vol.

. 3, pp. 26-32, New York : Springer-Verlag, 1967.

10. Kelly, M. G., O'Gara, R. W., Walker, M. D., Dawe, C. J.,

2036 CANCER RESEARCH VOL.28

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Choriocarcinoma Heterotranspiantation

Morgan, W. D., and Kerber, W. T. Intracerebral Transplantstion into Rhesus Monkeys of Cell Cultures (NCLP-6) DerivedFrom a Chemically Induced Primate Hepatocarcinoma. J.Natl. Cancer Inst., $9: 153—169,1967.

11. Kilnefelter, H. F., Jr., Aibright, F., and Griswold, G. C. Experience with a Quantitative Test for Normal or DecreasedAmounts of Follicle Stimulating Hormone in the Urine inEndocrinological Diagnosis. J. Chin. Endocrinol. Metab., 3:529—544,1943.

12. Kull, F. C. An Unsuccessful Attempt to Grow Human Tumorsin Monkeys. Transplant. Bull., 57: 103—104,1961.

13. Levey, R. H., and Medawar, P. B. Nature and Mode of Actionof Antilymphocytic Antiserum. Proc. Natl. Acad. Sci. U. S.,56:1130—1137,1966.

14. Monaco, A. P., Wood, M. L., Gray, J. G., and Russell, P. S.Studies on Heterologus Anti-lymphocyte Serum in Mice. II.Effect on the Immune Response. J. Immunol., 96: 229-238,1966.

15. Monaco, A. P., Wood, M. L., and Russell, P. S. Adult Thy

mectomy : Effect on Recovery from Immunologic Depressionin Mice. Science, 149: 432..42.@,1965.

16. Ross, G. T., Hammond, C. B., Hertz, R., Lipsett, M. B., andOdell, W. D. Chemotherapy of Metastatic and NonmetastaticGestational Neoplasms. Texas Rept. Biol. Med., 54: 326-338,1966.

17. Russell, P. S., and Monaco, A. P. The Biology of Tissue Trans..plantation. New Engl. J. Med., 571 : 502—510,1964.

18. Starzl, T. E., Marchioro, T. L., Porter, K. A., Iwasaki, Y., andCerilli, G. J. The Use of Heterologous Antilymphoid Agentsin Canine Renal and Liver Homotransplantation and in Human Renal Transplantation. Surg. Gynecol. Obstet., 124: 301—318, 1967.

19. Tow, W. S. H., and Cheng, W. C. Recent Trends in Treatmentof Choriocarcinoma. Brit. Med. J., 1: 521—523,1967.

20. Woodruff, M. F. A., and Anderson, N. F. The Effect of Lymphocyte Depletion by Thoracic Duct Fistula and Administration of Antilymphocytic Serum on the Survival of Skin Homografts in Rats. Ann. N. Y. Acad. Sci., 120: 119-128, 1964.

2037OCTOBER 1968

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J. L. Lewis, Jr., W. E. Brottiz, Jr., R. Hertz, R. C. Davis, and R. H. Johnson, Jr.

Fig. 1. Photomicrograph of human choriocarcinoma growing in brain of an adult rhesus monkey. Area of hemorrhage lies betweenthe tumor and cortex, but there is little cellular reaction. H & E, X 100.

Fig. 2. Coronal sections of the brain of a cynomolgus monkey inoculated with human choriocarcinoma as a newborn. Gross distortion of ventricles and shift of midline is evident. Histologically, this was typical choriocarcinoma as noted in Fig. 1.

2038 CANCER RESEARCH VOL. 28

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1968;28:2032-2038. Cancer Res   John L. Lewis, Jr., Willis E. Brown, Jr., Roy Hertz, et al.   Heterotransplantation of Human Choriocarcinoma in Monkeys

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