Behring Inst. Mitt., No. 74, 343-3S2 (1984)
`
`Comparison of Tumor Response in N ude Mice and in the Patients
`H. H. FIEBIG\ C. SCHUCHHARDT,' H . H ENSS,' L. FIEDLER/ G. W. L0 HR1
`
`1 Department of Internal Medicine, Medical Clinic, University of Freiburg i. Br., D-7800 Freiburg, HugstetterStr. SS,
`W.-Gennany
`2 Surgical Clinic, University of Freiburg i. Br., D-7800 Freiburg, W.-Germany
`
`Summary
`
`In 34 tumors of different origin 50 comparisons between the tumor response in the patients and in
`nude mice were performed. Combination chemotherapy was more success[ ul than single agent
`chemotherapy. Out of the 25 combinations giv en, 9 (36%) effected a remission in comparison to
`4 out of 25 (16%) after single agent chemotherapy. 13 patients got a remission which was found in
`12 cases in the nude mouse, too. 37 patients did not respond to treatment and the same result was
`found in 36 cases in the nude mouse system. Xenografts gave a correct prediction for resistance in
`97% and for tumor response in 92%. Despite great efforts to obtain a large number of com(cid:173)
`parisons, only 22 test results were available before the patients needed chemotherapy. In 13 cases
`chemotherapy was done simultaneously in the patient and in the nude mouse system. Jn 15 cases
`the patients were treated fi'fst. The xenograft system will not have practical significance in deter(cid:173)
`mining the treatment of the Plltients. limitations are the duration of the testing, the testing rate
`of about 50% and the charges for nude mice. However, the highly correct prediction rates for
`tumor sensitivity and resistence validates human tumor xenografts as tumor models to test new
`drugs and combinations.
`
`Int roduction
`
`The response rates of the different human
`cancers to antineoplastic chemotherapy are
`well known today. De Vita divided them in
`four categories: advanced tumors
`- which 'can be cured in part
`- which show an increase in life span
`- which show tumor regression in part
`without increase in life span
`- without tumor response (De Vita, 1982).
`
`We know the probability for a patient to re(cid:173)
`spond to a given treatment. However for an
`individual case we cannot predict if a patient
`would benefit from the treatment.
`
`Several in vitro methods have been employed
`in order to select compounds which would be
`effective against a given tumor. These include
`long term culture and evaluation of mor(cid:173)
`phological changes (Limburg and Krahe,
`1964), biochemical assays with inhibition of
`DNA or RNA synthesis (Volm et al., 1978,
`
`1980) or the in vitro colony formation where
`the colony number of the untreated controls
`and of the treated groups are compared (Sal(cid:173)
`mon et al., 1980; Von Hoff et al., 1981). These
`in vitro systems had a highly correct predic(cid:173)
`tion for tumor resistence (Volm et al., 1978;
`Salmon et al., 1980). However, no system
`got a clinical significance in order to select the
`drugs for the treatment of the patient.
`
`With the advent of the athymic nude mouse
`human tumors have grown successfully in
`these T-lymphocytes lacking animals. The
`human tumor-nude mouse model can be
`exploited to determine the individual response
`of a tumor and also to test new drugs and new
`combinations. This in vivo system presents
`advantages in comparison to in vitro expo(cid:173)
`sure. Drugs which must be activated or d~to­
`xified can be tested and also drug combina(cid:173)
`tions can be evaluated. In this paper we will re(cid:173)
`port on our take rates of 280 different human
`tumors after subcutaneous transplantation in
`
`1 of 10
`
`Celltrion, Inc., Exhibit 1026
`
`

`

`344
`
`H. H. Fiebig, C. Schuchhardt, H. Henss, L. Fiedler, G. W. Lohr
`
`nude mice and the comparison of tumor re(cid:173)
`sponse in nude mice and in the patients. The
`advantages and limitations of the xenograft
`system will be discussed.
`
`Methods
`
`Animals
`Athymic nude mice of the NMRI genetic
`background were used when being 6 to 10
`weeks old. They were bred in our own nude
`mouse colony. The animals were kept in mac(cid:173)
`rolon cages set in laminar flow rackets. They
`were maintained as described by Fortmeyer
`(1981). Tumors from men were implanted
`into male nude mice, tumors from women
`into fem ale animals.
`
`Tumors
`Within the last four years 309 resected human
`malignancies have been implanted subcutane(cid:173)
`ously into nude mice. 280 tumors were evalu(cid:173)
`able. The remaining received radiotherapy
`prior to surgery or no viable tumor tissue was
`present in our tumor sample. Tumor slices of
`5 x 5 x 0.5 to 1 mm diameters were implanted
`subcutaneously in the flanks of the animals, in
`the first passage usually 16 fragments into 4
`nude mice. When the tumors reached diamet(cid:173)
`ers of 1 to 1.5 cm they were subpassaged and
`the remaining tumor material was studied his(cid:173)
`tologically. In therapeutic experiments two
`tumors were implanted into each animal.
`
`Experimental design of testing
`Testing was done in serial passages usually be(cid:173)
`tween passage 2 and 6 when the growth be(cid:173)
`came more regular. In the first passage the
`growth behaviour was too different (Fiebig,
`1983; Fiebig and Lohr, 1984), the histological
`examinations at the time of randomisation
`showed that some tumors contained more
`fibrous'tissue than tumor cells resulting in a
`great variation of the tumor growth in the con(cid:173)
`trol as well as in the treated group.
`Mice were randomised to the untreated con(cid:173)
`trol or the test groups after 3 to 6 weeks when
`the tumors presented the following proper(cid:173)
`ties: product of the 2 tumor diameters was at
`least 10 mm2
`, the estimated depth was at least
`half of the smaller diameter. Tumors with a
`yellow colour, reflecting a high amount of
`fibrous tissue, were excluded. Using these
`criteria we never observed a spontaneous re(cid:173)
`gression or a stationary growth behaviour in
`the untreated control groups of the different
`xenografts after 3 to 4 weeks.
`At the time of randomisation the median
`product of the tumor diameters was 56 mm2•
`Each test group consisted of 5 to 6 animals,
`which contained between 6 to 10 evaluable
`tumors. At the time of randomisation several
`representative tumors were examined his(cid:173)
`tologically. When the tumors reached diamet(cid:173)
`ers of at least 15 and 10 mm, the experiment
`was finished, according to the growth velocity
`after 4 to 10 weeks. Each tumor had to double
`its initial tumor size at the end of the experi(cid:173)
`ment.
`
`Tum or growth measurements
`In therapeutic experiments tumor growth was
`followed weekly by measuring two perpen(cid:173)
`dicular diameters. The product of the 2
`diameters was taken as a measure for tumor
`size. Relative tumor size values were calcu(cid:173)
`lated according to tumor size day X divided by
`tumor size day 0 at the time of randomisation
`multiplied with 100.
`
`ChemotheraP'J
`The 34 patients were treated with the estab(cid:173)
`the single agent
`lished combination or
`chemotherapy. After progression of the initial
`therapy a second line therapy was given in 1.6
`cases. When a remission was found in the
`xenograft system the patient was treated with
`this drug initially.
`
`2 of 10
`
`Celltrion, Inc., Exhibit 1026
`
`

`

`Predictivity of Xenografts
`
`345
`
`The mice were treated in schedules which
`were similar as in the clinic. The drugs, doses,
`schedules and route of application are shown
`in Table 1. Usually the mice received 2 treat(cid:173)
`ment cycles in a 2 weeks interval. A dose
`around the LD20 after 28 days was considered
`as a maximal tolerable dosis. In combination
`
`chemotherapy the drugs were given in inter(cid:173)
`vals of 15 minutes at a different route in order
`to avoid direct interactions of the drugs. In 2-
`drug combinations only 70 -80% of the dose
`from single drug therapy could be given, in 3-
`drug combinations 50-60%, respectively.
`
`Table 1 Dose, schedule, administration and lethality of anticancer drugs in tumorbearing nude mice
`
`Drug
`
`Dose
`mg/kg/day
`
`Schedule
`day
`
`Appli-
`cation
`
`ACNU
`
`Adriamycin
`
`CCNU
`
`Cisplatin
`
`Dianhydro-
`galactitol
`
`1, 15
`1, 15
`1, 15
`
`1, 15
`1, 15
`1, 15
`
`20
`
`8.0
`6.0
`6.0
`
`20
`
`8
`8
`10
`8
`
`4
`
`ip
`
`iv
`iv
`ip
`
`ip
`
`SC
`ip
`ip
`SC
`
`pos
`
`Day14
`
`death/total
`
`15/125
`
`3/ 32
`01 16
`3/ 23
`
`14/103
`
`9 / 52
`21 20
`8 1 32
`41 43
`
`Day28
`
`death/total
`
`%
`
`23/125
`
`71 30
`3/ 16
`9/ 23
`
`15/103
`
`12/ 52
`2 / 20
`9 / 32
`51 42
`
`71 39
`
`18
`
`23
`19
`39
`
`15
`
`23
`10
`28
`12
`
`18
`
`%
`
`12
`
`9
`0
`13
`
`14
`
`17
`10
`25
`9
`
`15
`
`DTIC
`
`Etoposid
`(VP-16)
`
`Fluoruracil
`
`HECNU
`
`Mitomycin-C
`
`Vindesin
`
`1-4
`
`1-4, 15-18
`
`1-3, 15-17
`1-3
`1-3
`1-3, 15-17
`
`1-4, 15-18
`1-4, 15-18
`1-4, 15-18
`1, 8, 15
`1, 8, 15
`
`1, 15
`1, 15
`
`1, 8, 15
`1, 8, 15
`1, 8, 15
`
`80
`
`30
`30
`40
`25-32
`
`40
`50
`63
`100
`125
`
`12
`15
`
`2.5
`2.5
`
`1.5
`1.5
`2.0
`
`ip
`
`SC
`SC
`SC
`ip
`
`Ip
`Ip
`ip
`ip
`Ip
`
`Ip
`ip
`
`iv
`ip
`
`iv
`ip
`ip
`
`61 39
`
`01 22
`
`2/ 27
`2 / 29
`5/ 9
`6/ 20
`
`19/ 157
`1 / 5
`8/ 15
`Of 25
`41 10
`
`2/ 21
`61 36
`
`10/ 50
`61 45
`
`81 91
`1/ 18
`71 21
`
`0
`
`7
`7
`56
`30
`
`12
`20
`53
`0
`40
`
`10
`17
`
`20
`13
`
`8
`6
`33
`
`2 / 22
`
`3 / 27
`2/ 29
`61 9
`9/ 20
`
`27/157
`1 / 5
`9 / 15
`2/ 25
`41 10
`
`41 21
`81 36
`
`14/ 50
`17/ 45
`
`10/ 91
`3 / 18
`10/ 21
`
`9
`
`11
`7
`67
`45
`
`17
`20
`60
`8
`40
`
`19
`22
`
`28
`38
`
`11
`17
`48
`
`The maximal tolerable dose (MTO) is framed.
`
`3 of 10
`
`Celltrion, Inc., Exhibit 1026
`
`

`

`346
`
`H. H. F~big, C. Schuchhardc, H. Henss, L. Fiedler, G. W. Lohr
`
`Evaluation parameters for tumor response
`In nude mice evaluation was done after maxi(cid:173)
`mal tumor regression, usually after 3 to 4
`weeks. The effect of treatment was classified
`as remission (product of two diameters less
`than 50% of initial value), minimal regression
`(51 - 75%), no change (76- 124%) and pro(cid:173)
`gression (2:: 125% of initial value). All patients
`had well measurable lesions, they were treated
`and followed as in clinical trials. The evalua(cid:173)
`tion of tumor response in nude mice and in the
`patients was done by different physicians.
`
`Results
`
`Take rates and growth behaviour
`
`A critical point is the take rate and the fre(cid:173)
`quency of tumors which grow progressively
`and can be transferred to serial passages. These
`tumors only are suitable for testing. Out of the
`total of 280 human malignancies 211 (75%)
`showed a tumor take presenting viable tumor
`tissue in the nude mouse as proven by his(cid:173)
`tological examination. A rapid tumor growth
`defined as tumor size of at least 60 mm2 (ax b)
`
`Table2 Take rate and growth behaviour of human malignancies after transplantation Into nude mioe
`
`Tumor
`type
`
`Total
`number
`
`Tumor
`take•
`
`Rapid
`growthb
`
`Slow
`growth•
`
`Serial
`passaged
`
`Colorectal canoers
`Stomach cancers
`Esophageal cancers
`Lung canoers
`-epldermold
`- adeno
`- smalloell
`Sarcomas
`- soft tissue
`-bone
`Melanomas
`Renal canoers
`- hypernephromas
`- W1lms-Tumors
`- neuroblastoma
`- pelvis cancer
`Testicular cancers
`Cane. of head and neck
`Miscellaneous tumors
`
`28
`16
`6
`
`16
`4
`
`83
`44
`6
`50
`
`20
`
`19
`
`17
`3
`
`1
`11
`5
`20
`
`n
`
`65
`30
`5
`
`22
`14
`5
`
`12
`4
`17
`
`10
`3
`
`1
`4
`4
`14
`
`%
`
`78
`68
`83
`
`79
`88
`83
`
`75
`
`89
`
`59
`
`36
`80
`70
`
`n
`
`41
`14
`5
`
`17
`9
`3
`
`9
`1
`
`9
`
`6
`2
`0
`
`4
`
`2
`7
`
`%
`
`49
`32
`83
`
`61
`56
`50
`
`56
`
`47
`
`35
`
`36
`40
`
`35
`
`n
`
`24
`16
`
`0
`
`5
`5
`2
`
`3
`3
`8
`
`4
`1
`1
`0
`0
`2
`7
`
`%
`
`29
`36
`
`18
`31
`
`19
`
`42
`
`24
`
`40
`35
`
`n
`
`46
`17
`4
`
`19
`8
`3
`
`9
`
`8
`
`6
`1
`0
`1
`2
`2
`8
`
`%
`
`55
`39
`67
`
`68
`50
`50
`
`56
`
`42
`
`35
`
`18
`40
`40
`
`Total
`
`280
`
`211 75%
`
`130 46%
`
`81
`
`29%
`
`135 48%
`
`a • Htstologlc d9monstr adon of viable tumor bssue
`b • Tumor Ille (a x b) or at least 1 tumor ~ 60 mm2in1he first passage after 90 days
`C MS 59mm1
`d • COnbnUOUI growth of at leas1 3 passages..
`
`4 of 10
`
`Celltrion, Inc., Exhibit 1026
`
`

`

`Predictivity of Xenografts
`
`347
`
`after 90 days was observed in 130 tumors
`(46%) and a slow growth in 81 tumors (29%).
`Most of the rapidly growing tumors and in
`rare cases also initiaJJy slowly growing tumors
`were transferred to serial passages. 135 malig(cid:173)
`nancies (48%) were subpassaged at least three
`times. These high take rates were initiaJJy
`found in colorectal cancers only. After refine(cid:173)
`ment of the technique, e.g. selection of viable
`tumor tissue, similar take rates were observed
`in the other malignancies, too (Table 2). 126
`regularly growing tumors of different tumor
`categories were selected as tumor models.
`Most of them are frozen in liquid nitrogen and
`are available for therapeutic and tumor biolog(cid:173)
`ical studies (Fiebig, 1983; Fiebig and Lohr,
`1984).
`
`Comparison of tumor response
`
`In 34 tumors 50 comparisons between the
`tumor response in the patients and in nude
`mice were performed. In co1orectal cancers 19
`comparisons were done with single agent
`chemotherapy, usually 5-Fluoruracil or a ni(cid:173)
`trosourea, and
`three with combination
`chemotherapy. Most of the other rumors were
`treated with combination chemotherapy (22)
`and 6 tumors with single agent chemotherapy.
`Stomach cancers were treated with the FAM(cid:173)
`combination (Fluoruracil + Adriamycin +
`Mitomycin-C). The treatment of the other
`tumors is indicated in Table 7 and 8.
`
`The overall result is given in Table 3. The total
`of 13 patients got a remission which was found
`in 12 cases in the nude mouse, too. 37 patients
`did not respond to treatment and the same re(cid:173)
`sult was found in 36 cases in the nude mouse
`system. Overall, xenografts gave a correct
`prediction for resistence in 97% and for tumor
`response in 92%.
`
`Table 3 Comparison of tumor response of various
`human malignancies in nude mice and in the
`patient
`
`Mouse I Patient
`
`Remission I Remission
`No Remission / Remission
`
`No Remission / No Remission
`Remission / No Remission
`
`Total
`
`12/12
`01 1
`
`36/ 36
`1 / 0
`
`50 compattsons in 34 tumors were performed. Xenogralts gave a
`correct prediction for resistanoe in 36137 (97% ), and for response in
`12113 (92%) cases.
`
`after single agent chemotherapy. Single agent
`therapy was successful in 3 colorectal cancers
`and in one stomach cancer. The tumor res(cid:173)
`ponse according to the tumor type is shown in
`Table 4. A detailed analysis of the given treat(cid:173)
`ment and the response is listed for colorectal
`cancers in Table 5, for stomach cancers in
`Table 6, for lung cancers in Table 7 and for the
`remaining tumors in Table 8.
`
`Most of the tumors were obtained at the time
`of surgery of the primary tumor. When the
`tumor was resected completely the time until
`development of distant metastases or local
`tumor recurrence aJJowed us to do the testing
`in the nude mouse. When the patient presen(cid:173)
`ted metastases at the time of tumor removal,
`the patients were treated with the established
`treatment of the rumor category. When the
`patient's tumor progressed under this chemo(cid:173)
`therapy a second line treatment was found in
`some cases in the xenograft system. Despite
`great efforts to obtain a large number of com(cid:173)
`parisons, only in 22 cases a result of the
`xenograft testing was available before the
`patients needed chemotherapy. In 13 cases
`chemotherapy was done simultaneously in the
`patient and in the nude mouse system, and in
`15 cases the patients were treated first.
`
`Combination chemotherapy was more suc(cid:173)
`cessful than single agent chemotherapy. Out
`of the 25 combinations given, 9 (36 % ) effected
`a remission in comparison to 4 out of 25 (16%)
`
`An example of the identical response of the
`thyroid cancer XF 117 to the combination of
`Cyclophosphamide, Vincristin, Adriamycin
`and DTIC in the patient (lung metastases) and
`
`5 of 10
`
`Celltrion, Inc., Exhibit 1026
`
`

`

`348
`
`H. H . Fiebig, C. Schuchhardt, H . Henss, L. Fiedler, G. W. Lohr
`
`Table 4 Comparison of tumor response, according to tumor category in nude mice and in the patient
`
`Mouse I Patient
`
`Colorectal
`cancer
`
`Stomach
`cancer
`
`Lung
`cancer
`
`Mela-
`no mas
`
`Miscellaneous
`malignancies•
`
`· Remission I Remission
`No Remission I No Remission
`No Remission I Remission
`Remission/No Remission
`
`Total
`
`2
`19
`1
`0
`
`22
`
`4
`5
`0
`0
`
`9
`
`a = Soft tissue sarcomas, thyroid cancer, Wllms-lumor. cancer of the penile
`
`2
`6
`0
`0
`
`8
`
`0
`3
`0
`
`4
`
`4
`3
`0
`0
`
`7
`
`Tables Comparison of tumor response of human colorectal cancers in the patient and in nude mice (n = 22).
`Individual cases
`
`Tumor
`CXF
`
`Evaluation parameter
`metastases of
`
`Therapy
`
`Effect
`
`nude mice
`
`patient
`
`158
`
`280
`164
`
`207
`
`264
`
`268
`269
`270
`
`288
`90
`167
`210
`
`248
`273
`
`Lung
`
`Skin, Brain
`Lung, Peritoneum
`carcinosis
`
`Liver
`
`Liver
`
`Lung, Lymph node
`Lung
`Liver, Lung
`
`Liver, Lung
`Liver
`Liver
`Lung, Skin
`
`Lung, Bone
`Liver, Lung
`
`5-FU
`ACNU
`ACNU
`5 - FU+ BCNU+ VCA
`MTX
`PLAT
`ACNU
`5- FU
`ACNU
`5- FU
`ACNU
`5- FU
`HECNU
`5 - FU
`5 - FU
`FU+CY
`ACNU
`5 - FU+ MeCCNU+ VCR
`ACNU
`MITO
`5- FU
`5-FU
`
`p
`PR
`PA
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`
`NC
`PR
`PA
`p
`p
`p
`p
`p
`p
`PR
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`p
`
`CXF = Colotectal cancer Xenogratt Freibu~; VCR • Vincristm; MTX • Methotrexat: PLAT = Cisplatin; CY = Cyclophosphamide;
`MITO = Mitomycin-C; P = Progression: NC = o Change: PR • Partial Remiss!Ofl: CR = Complete Remission.
`
`6 of 10
`
`Celltrion, Inc., Exhibit 1026
`
`

`

`Predictivity of Xenografts
`
`349
`
`Table 6 Comparison of tumor response of human stomach cancers in nude mice and in the patient (n = 9)
`
`Tumor
`GXF
`
`Evaluation parameter
`metastases of
`
`Therapy
`
`Effect
`
`nude mice
`
`patient
`
`97
`
`180
`
`209
`236
`281
`324
`
`Recurrent tumor,
`CEA
`Liver
`
`Rec. tumor, LN
`Rec. tumor, LN
`Lymph nodes
`Rec. tumor, LN
`
`FAM
`CCNU
`FU+BCNU
`MITO
`VIND
`FAM
`FAM
`FAM
`FAM
`
`PR
`PR
`p
`NC
`p
`
`PA
`p
`
`PR
`p
`
`PR
`PA
`p
`NC
`p
`
`PR
`p
`
`PR
`p
`
`GXF • Gastric Cancer Xenograf\ Freiburg; FAM = FU + Adriamycin + Mitomycln·C; VIND • Vindesin; LN • Lymph Node; Further
`abbreviations see Table 5.
`
`Table 7 Comparison of tumor response of human lung cancers in nude mice and in the patient (n = 8)
`
`Tumor
`LXF
`
`Histology of the
`carcinomas
`
`Evaluation
`parameter
`metastases of
`
`Therapy
`
`Effect
`
`nude
`mice
`
`patient
`
`66
`
`126
`247
`
`331
`1n
`
`Epidermoid
`
`Bone, Skin
`
`Epidermoid
`Epidermoid
`
`Ade no
`Small cell
`
`Bone, Skin
`Lung, Skin
`
`Lung, Skin
`Lymph node
`
`VIND+ PLAT
`CY+ CCNU
`MACC-Comb.
`VIND+ PLAT
`VP-16
`
`HECNU
`A CO-Comb.
`VP- 16+ PLAT
`
`p
`p
`p
`p
`p
`p
`
`PR
`PR
`
`p
`p
`p
`p
`p
`p
`
`PR
`PR
`
`LXF • Lung cancer Xenograf\ Freiburg; VIND = Vindesin; MACC-Combination = MTX + Adriamycin + CY + CCNU; ACOCombonation =
`Adriamyan + CY + VCR; Further abbreviations see T ab4e 5.
`
`in nude mice is shown in Fig. 1. The 2 lung
`metastases showed a regression of more than
`50% after 2 treatment cycles. The testing in
`the xenograft system revealed that among the
`4 drug combination the only effective drug
`was DTIC.
`
`Discussion
`
`One purpose of this study was to evaluate if
`the xenograft system could have a significance
`
`in determining the responsiveness of the
`patient's tumor and furthermore, to validate
`the human tumor-nude mouse system for its
`potential to test new drugs. Advantages
`include the high correct prediction for resis(cid:173)
`tence and sensitivity of a tumor. The testing is
`reproducible and also combinations and drugs
`which must be activated or detoxified can be
`tested. Although the number of comparisons
`especially in responsive tumors is low, the
`higher correct prediction for sensitivity in
`
`7 of 10
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`
`

`

`350
`
`H. H. Fiebig, C. Schttchhardt, H. Hems, L. Fiedler, G. W. Lohr
`
`Tables Comparison of tumor response of various human malignancies in nude mice and in the patient
`
`Therapy
`
`Effect
`
`nude mice
`
`patient
`
`ACO
`
`p
`
`P- NC
`
`Tumor
`No.
`
`Localisation
`of the primary
`tumor
`
`SXF115
`
`Left ankle
`
`SXF 2 Right chest
`XF179 Penile
`
`Histology
`
`Evaluation
`parameter
`metastases of
`
`Lung, Skin
`
`Malignant fibrous
`histiozytoma
`Neurogenic sarcoma Lung
`Epidermoid cancer
`Skin, LK
`
`XF 111
`
`Right thigh
`
`Melanoma
`
`Skin
`
`XF154 Right shoulder
`XF274
`Foot
`
`Melanoma
`Melanoma
`
`Lung, Bone
`Lung,LK
`
`XF276 Right shoulder
`XF117
`Thyroid ea
`XF162 Right kidney
`
`Melanoma
`Anaplastic cancer
`Wilms-Tumor
`
`Lung, Bone
`Lung
`Lung
`
`p
`
`PR
`
`p
`
`p
`
`ACO
`PLAT+Velbe
`+BLEO
`DTIC+VCR+
`BLEO+ Hydroxy-
`urea
`VCR+CCNU
`PLAT+VIND+
`BLEO
`PLAT+VIND
`CR
`CYVADIC
`CR
`ACO
`CY+CCNU+VP-16CR
`
`PR'
`
`p
`
`NC
`PR
`
`p
`
`p
`p
`
`p
`
`PR
`PR
`CR
`
`SXF • Sarcoma Xenografl Freiburg; a= Progression in Passage 3; CYVADIC = CY+ VCR + Adriamycin + DTIC:
`Further abbreviations see Table 5.
`
`comparison to in vitro systems must be poin(cid:173)
`ted out. In the stem cell assay and in the bio(cid:173)
`chemical assay only half to two thirds of the
`predicted effective drugs were active in the
`clinic (Salmon et al., 1980; Volm et al., 1978).
`A better prediction for effective drugs was
`reported in xenograf t systems by Shorthouse
`et al. (1980).
`
`However, in our opinion the xenograftsystem
`will not have practical significance for the
`treatment of the patients. Limitations are the
`duration of the testing which can only be done
`in serial passages so that 4 to 8 months are
`needed to obtain a result. Nude mice are ex(cid:173)
`pensive, they need special conditions behind
`laminar flow barriers to avoid infections. A
`limiting factor is also the testing rate because
`only half of the implanted tumors can be
`transferred to serial passages. Whereas the
`xenograft system cannot be used as a clinical
`routine method, the highly correct prediction
`
`for tumor sensitivity and resistence ·validates
`human tumor xenografts as tumor models to
`test new drugs.
`
`A critical question is if the dosages used in the
`mouse are relevant for the clinic, too. A com(cid:173)
`parison of the maximal tolerable dosis in dif(cid:173)
`ferent animal species and in man demonstrated
`that a reasonable comparison can be made
`when the dose is based on body surface
`(Freireich et al., 1966). However, for some
`drugs there also seem to be exceptions. Using
`Fluoruracil the man tolerates three times the
`dose of mice and the effect of this drug seems
`to be underestimated in the xenograft system.
`Furthermore, Fluoruracil effected no remis(cid:173)
`in 12 stomach and 23 colorectal
`sion
`xenografts, whereas in the clinic the remission
`rates are 20%, respectively. Further com(cid:173)
`parisons with responsive tumors are needed to
`see if lower criteria for activity in the xenograft
`system will allow to test this drug.
`
`8 of 10
`
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`
`

`

`Predictivity of Xenografts
`
`351
`
`Chemotherapy of XF 117/5
`
`Chemotherapy of XF 117 /5
`
`3 r-.--.--.--.-.--~~~~~~--,-L.-'.--.-~~.....--.--··
`0
`M
`~
`~
`Days after Randomisation
`
`a)
`
`"' & I
`
`b)
`
`Days after Random I satl on
`
`Chemotherapy (CYVADIC> of the Pat. D.E.
`with advanced thyroid cancer 117
`
`Chemotherapy ICYVADIC) of the Pat. D.E.
`wl th advanced thyroid cancer 117
`
`!ill'"
`
`Jhu.,.
`
`r~
`ru \~ ~·
`~BcaloH•taotaolo
`
`c)
`
`6.=Hetaatas1s right chest,+= Hetaatasis left hilus
`
`Days after Beginning of Therapy
`
`Days after Beginning of Therapy
`a.= Heta11ta11111 right che11t,
`.. = Heta11tasls lert hllu11
`d) g~~r~~~0 ~g/m' VVCA 1 111g/l'll~
`•ADA 50 mg/m 1
`.i,.oTIC 200 resp • .i,.133 •g/m'
`
`e)
`
`f)
`
`Fig. 1: Response of the thyroid cancer 117 to the combination of Cyclophosphamide + Vincristin + Adriamycin +
`DTIC. a) and b) Growth curves in the nude mouse to the 4-drug combination and the single drugs; c) and d) Growth cur(cid:173)
`ves of 2 lung metastases; e) and f) X-Ray before treatment and after 2 cycles.
`
`9 of 10
`
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`
`

`

`352
`
`H. H. Fiebig, C. Schuchhardt, H. Henss, l. Fiedler, G. W. Lohr
`
`Acknowledgements
`
`We wish to thank Prof. Dr. E. H. Farthmann
`and formerly Prof. Dr. M. Schwaiger (Direc(cid:173)
`tors of the Chirurgische Universitatsklinik,
`Freiburg) for sending us human tumor tissue.
`We would like to thank our collaborators Miss
`C. Berg, U. Dentler, K. Meinhardt and Dipl.(cid:173)
`Ing. K.-H. Widmerfortheir competentassist(cid:173)
`ance in this project. This work was supported
`by grant PTB 8466 from the "Bundesministe(cid:173)
`rium for Forschung und Technologie".
`
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`Lippincott Company, Philadelphia, Toronto.
`Limburg, H. & Krahe, M. (1964) Ziichtung von menschli(cid:173)
`chcm Krebsgewebe in der Gewcbekultur und seine Sensi(cid:173)
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`
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`
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`
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`
`Fiebig, H. H. (1983) Wachsrum und Chemotherapie
`menschlicher Tumoren - vorwiegend Dickdarm-, Ma(cid:173)
`gen- und Bronchlalkarzinome -
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`
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`
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`
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`10 of 10
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`