[CANCERRESEARCH30, 430—438,February1970] Experimental Investigations with 1-(Morpholinomethy1)4-phtha1imido@ piperidindione-2 , 6 and Drostanolone Propionate in Dimethylbenz anthracene-induced Tumors of Sprague-Dawley Rats

H. M(ickter, E. Frankus,and E. More Research Laboratories, Chemie, Griinenthal GmbH, Stolberg/Rheinland, Germany

SUMMARY use of the tumors as parameters) the general condition and survival time of the animals treated had our special atten The survival time of rats with 7 , l2-dimethylbenzanthra tion. Rooks and Dorfman (5) have studied the survival time cene-induced tumors is significantly increased by treatment of Sprague-Dawley rats bearing transplanted mammary fibro with the combination of the cyclic imide l-(morpholino adenomas. They found a significant extension of the survival methyl)-4-phthalimido-piperidindione-2 , 6 and drostanolone time under treatment with drostanolone. propionate (2a-methyl dihydrotestosterone propionate). In The following is a report on our long-term observations in long-term treatment the antitumor activity, determined by DMBA-induced mammary tumors in Sprague-Dawley rats the number of the tumor centers, is likewise significantly treated with the cyclic imide CG 603 , the steroid drostano increased compared with the effect of the combination lone propionate, and the combination of both these active components alone. substances.

INTRODUCTION MATERIALS AND METHODS

In an earlier publication (4) we reported in detail that in The essential details have been described in our earlier relatively high doses the cyclic imide l-(morpholinomethyl) reports (3, 4). We define the effect on the tumors by 4-phthalimido-piperidindione-2 , 6 has a sustained effect on counting the number of tumor centers, as this parameter has 7 , 12-dimethylbenzanthracene-induced tumors in Sprague shown itself to be the most reliable criterion . We have Dawley rats; simultaneously, the body weight of the animals defined as tumor center any palpable tumor formation. is reduced in relation to the CG 603' dosage. Measurable tumors are those which can be measured percu In a further publication (3) we established a more or less taneously with sliding calipers. In determining the tumor similar antitumor effect to be achieved without any reduc area we measured the largest and smallest diameters of the tion in body weight when CG 603 is combined in relatively tumors palpable percutaneously. The product of these figures low doses with the androgen drostanolone propionate in was used as the parameter of the actual size of the tumor. doses which nearly correspond to those used in the treat Gross body weight means the weight of the animals plus ment of human mammary carcinoma. For these investiga tumor weight , whereas net body weight is body weight tions the animals were observed over a total period of 8 minus tumor weight. Weight of the tumors was calculated weeks = 56 days, calculated from the first day of treatment. according to the formula (length X width (squared)),2 (3). The In the following we report on observations carried out to significance of the survival times of each group in relation to ascertain the survival time of treated and untreated animals each other was determined by the Student t-test (6). How with DMBA-induced tumors. In order to be able to judge the ever, we have modified the schedule of treatment in view of antitumor effect we selected the number of tumor centers as the clinical investigations which have been started on humans criterion. It can be learned from experiments with animals in the meantime. In Test A treatment in all test groups was and experience from human tumors, however, that decrease interrupted between the 56th and 98th day (“pause―test). in tumor number and size was not necessarily associated In Test B all animals with the exception of the controls with clinical benefit to the animal or the patient (2). With (Group 1) were first treated for 8 weeks = 56 days our therapeutic measures we are, above all, striving for a (beginning of “escape―)withdrostanolone propionate alone significant prolongation of life , as long as it is not possible (1 mg 3 times/week s.c.). On the 57th day we selected from to reach a complete cure resulting in a feeling of well-being the primary pool of animals 4 groups, each consisting of 20 which is as pronounced as possible. For this reason (besides animals, with nearly identical numbers and sizes of tumors. One of these groups, Group 2, received drostanolone pro pionate alone in the above-mentioned concentration, while the other 3 were treated additionally with CG 603 (Table 1). 1 ‘l'ha abbreviations used are: CG 603, 1-(morpholinomethyl)- After the first 56 days 3 of 20 untreated animals (Group 4-phthaliinido-piperidindione-2,6;DMBA,7,12-dimethylbenzanthracene. 1) had died. Therefore, only 17 animals were available as Received April 1, 1969; accepted June 24, 1969. controls.

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Table 1

Classification of experimental groups by method of treatment

of GroupNo.treatment1(control)17NoneNone220DrostanoloneanimalsBasic treatmentAdditive

propionate, 1 mg/animal times/wkNone320Drostanolone s.c. 3 603 in 0.25% pellets continually420Drostanolone propionate, 1 mg/animal s.c. 3 times/wkCG 603 in 0.25% pellets propionate, 1 mg/animal intermittently, i.e., s.c. 3 times/wkCG 4 wk treatment followedby 2 wk treatment520Drostanolone without 603 in 0.1% pellets propionate , 1 mg/animal continually s.c. 3 times/wkCG

RESULTS propionate slightly prolongs the life of the tumor animals under the test conditions described. However, a significant Table 2 shows the numbers of DMBA-induced tumor and prolonged extension of survival time is achieved by a centers in the course of treatment for 154 days 22 weeks, combined treatment with CG 603 plus drostanolone propio with interruption of treatment between the 8th and 14th nate. The difference in survival time between the drostano week (Test A). While more than 7 tumors per animal lone group and the group with combined treatment is develop in the untreated controls, the number of tumor statistically significant. The experiment was concluded after centers remains more or less constant with CG 603 as well as 201 days when all animals of the control group had died. At with drostanolone propionate . After discontinuation of treat this time 2 of the drostanolone animals and I of the CG 603 ment in the drostanolone group following a latent period of animals were still alive, while 9 out of the 20 animals in the 4 weeks the number of tumor centers increases and keeps combination group were still living. increasing even after resumption of treatment. However, in In the postmortem examinations of all animals, pneumonia the CG 603 group the interruption of treatment does not was predominantly diagnosed by the pathologist as the cause result in any difference in terms of later responsiveness of of death. Metastases in the lung were not found. The type of the tumor to CG 603. Treatment interruption indeed results pneumonia seen was encountered in the treated as well as in in a slight increase of the number of tumor centers, but with the untreated group of tumor animals. resumption of treatment the number of tumor centers does Table 4A shows the behavior of tumor centers under the not increase any further. On the other hand the combined treatment with drostanolone propionate in comparison to treatment causes a significant numerical reduction of the the untreated controls. After 8 weeks a number of the tumor centers. However, interruption of treatment leads to drostanolone animals were additionally given CG 603, as just as marked an increase in tumor centers after a certain described in detail under “Materialsand Methods.― From latent period. The resumption of treatment again brings Table 4B it can be seen that additional treatment with CG about a reduction of the number of tumor centers although 603 following 8 weeks pretreatment with drostanolone this occurs more slowly and less clearly in contrast to the propionate causes an increase in effect against the tumors. initial treatment. The difference in tumor centers between The decrease in number of tumor centers in the groups the control group and the treated groups is statistically under combined treatment, compared with tumor centers of significant . Between the group treated with the combination animals being treated with drostanolone propionate alone, is of drostanolone propionate and CG 603 and the groups statistically significant. The continuous treatment influences treated with drostanolone propionate and CG 603 alone, the tumor centers to a higher degree than the treatment in respectively , only in the 14th and 16th week is no difference intervals (I .90:3.08). seen. This apparently is due to the interruption of treatment Chart 2 shows the survival rates of the controls and the between the 8th and 14th week. treated groups in Test B. Table 5 shows the mean values of Chart 1 shows the survival rates of the controls and the survival days calculated on the basis of 50, 25, and 0% treated groups. Table 3 shows the mean values of survival survivors. On the 25% and 0% bases the animals still alive are days calculated on the basis of 50, 25 , and 0% survivors. On considered as having died on the 224th day. Drostanolone the basis of 0% survivors the animals still alive are regarded propionate given alone prolongs the life of the tumor as if they had died on the 201st day. In comparison with animals only to an insignificant extent as is evident from the untreated controls it can be seen that drostanolone Chart 2 and Table 5 , compared with the survival time of the

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‘0 0 In ‘0 (@,In ‘1' 0 0 untreated controls. On the other hand the combination of 44 @11 44 .1, Sn CG 603 in both concentrations and drostanolone propionate Ii 00 I. results in a significantly prolonged survival. It does not seem

‘0 00 (@1 ‘0 to make any difference with regard to survival time whether (‘IIn 0 0 the treatment with CG 603 pellets is added to the dro 44 +1 I,' r@ stanolone treatment only in intervals or continually. The I, I.. experiment was concluded after 224 days when all animals

I.. 00 In of the control group had died. At this time 5 out of 20 I In (@, In ‘OIn @ 0 o@ ei animals of the drostanolone group were stifi alive, while in +1 +i8 41@ 8 00 the combination groups, of those receiving 0.25% pellets 0 continually 10 out of 20 were stifi living; of those receiving 8 0.25% pellets at intervals 10 out of 20 were still alive; and I... ,•, @In 1V@In @ 0 0@ of the group receiving 0.1% pellets continually 4 out of 20 +4 448 0 e4 ‘0 were still living. a ‘0 Again, pneumonia was predominantly diagnosed as the

(‘I I'b cause of death. I I.. ‘*In 0 o2 In Table 6 the percentage of changes in gross and net body +4 +4@ +1 @ 00 weight (Test A) is given, in relation to the average weight at 8 C,) 0 C 00@ +4 I. ei the start of the experiment. Whereas the gross body weight 0 of the untreated controls shows a steady increase in the ‘0 ‘I In G' .0 E (.4In In In 0 0 o@2 0 course of the experiment the net body weight remains near +1 +4 +4@@ +1 the initial values and shows a tendency to decrease toward @ 0 ‘0 00d F.. 0Dvv 00@ ‘a 0 the end of the test. The weight curves of the animals treated C V with CG 603 alone correspond to those of the control 0 @In 0 group. The drostanolone propionate-treated animals show a V +1 +4 .@ 00 marked weight increase caused by the anabolic effect of the ‘1 V compound. The difference growing in the course of the 0 0 z C.. ‘0 experiment between gross body weight and net body weight ‘1 0 0 0 0 can be interpreted as the actual increase of weight of the +4 41. +4. 8 +4. ‘I 0 In In C.- tumors. The increase of gross body weight in the group @ ei Cl In 0 (.4 V o treated with the combination corresponds to that of the 0 00 In 0 group treated with drostanolone propionate alone. However, 0 0 0 0 +4 41. +4. 8 +4@ there is no clear difference between gross and net body 0 In 0 00 weight in the group treated with the combination as not In 0 (.4 only does the number of tumor centers remain low (Table 2) In I.. (.4 In but also the tumor weights do not show an increase under 0 0 0 the treatment with the combination. H +4. +4. 8 In In 0 In Table 7 the corresponding figures for Experiment B are (.1 0 given . In this setup the reference value of animal weight is

0' 0' 0 C.. (.4 the weight after 8 weeks pretreatment with drostanolone 0In ‘1 0 0 In 0 propionate. These animals do not show any major increase in 41 +4. q •41 In In body weight. The general trend in the figures of animal (.4 weight demonstrable from Table 7 corresponds to that of

‘0 C.. 0 (.4 en (.4 en Experiment A (Table 6). 0 0 0 +4 +4 +4 +4 In DISCUSSION (.4 (.1 The findings described seem remarkable for two reasons. As we reported in earlier publications, the antitumor activity of drostanolone propionate on the number of DMBA-induced 2 @a 0 tumors of Sprague-Dawley rats is significantly increased by 0 @22 @ ‘I V. additional treatment with the cyclic imide CG 603 . Further a experiments should show whether this effect is to be a@ regarded as additive or synergistic. This increase in activity .@.‘ •1 . can be seen when drostanolone propionate is combined with @ o.4 * the cyclic imide from the very beginning of treatment. This @‘ a@ @ .2@ : is still the case, although to a smaller extent, when the -@ @en .@ animals are treated with drostanolone propionate up to the @3..- o@ @ipoint when the effect of the drostanolone treatment begins

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Table 3 Averagelife-spancalculatedon variousrates ofsrirvival ofrats bearingDMBA-inducedtumors in response to treatment with drostanolone propionate, CG 603, and combination ofthe two days (mean ±S.E.) @ CompoundSurvivorspropior-@-―@Control5066.10± (%)Survival ±@iPcontrolaPdrostanolone 7.97Drostanolone propionate,1 10.19<0.05CGmg 3 times/wk s.c.87.90 ± 603,0.25%pellets70.80 12.26CG ± 603,0.25%+ propionate1drostanolone 12.99<0.0005<0.025Control2584.56±mg 3 times/wk s.c.124.30 ±

8.89Drostanolone propionate,1 11.28<0.05CGmg 3 times/wk s.c.110.60 ± 603,0.25%pellets90.73±11.07CG

603,0.25%+ propionate,1drostanolone 12.54<0.0005<0.025Control0104.50±10.78Drostanolonemg 3 times/wk s.c.148.40 ±

propionate,1 12.12<0.05CGmg 3 times/wk s.c.132.60 ± 603,0.25%pellets114.95 12.88CG ± 603,0.25%+ propionate,1drostanolone mg 3 times/wk s.c.161.55 ±10.68<0.0005<0.05

aStudent t-test.

Table 4A The development oftumor centers under treatment with drostanolonepropionate in comparisonto untreated controlanimals (PhaseI of Test B)

S.E.)0 tumor centers, Test B (mean ±

CompoundNo.wkControl2.85 wk2 wk4 wk6 wk8 0.71Drostanolone ±0.394.10 ±0.535.37 ±0.555.74 ±0.626.47 ± propionate,1 mg 3 times/wk s.c.2.85 ±0.342.65 ±0.342.60 ±0.312.65 ±0.302.70 ±0.23

to diminish (escape phenomenon). This fmding is of impor cantly under supplementary doses of CG 603. Rooks and tance when the compound is investigated in human patients. Dorfman described a significant increase in the survival time In this way, it is possible to differentiate the activity of of rats bearing transplanted mammary flbroadenomas and drostanolone from the additional effect of the cyclic imide. treated with drostanolone. In our investigations we were able The basic prerequisite for this is that the findings in the rat to achieve a relatively short prolongation of life with can be applied to the human mammary carcinoma. Further drostanolone propionate. alone; this was significant only in 1 more, the increase in effectiveness depends on the dosage of experiment. Even high doses of drostanolone propionate did the cyclic imide. The effect of the treatment is still to be not produce better results, as we learned from unpublished seen when the cyclic imide is discontinued for short tests. intervals, while the basis treatment with drostanolone is kept The body weight curve of test animals can be regarded as a on. This observation could be important if continued long suitable criterion for their general condition, and a certain term treatment were to lead to side effects by the cyclic correlation between the antitumor activity and the prolonga imide in humans. tion of survival time can be seen from the analysis of the net Another point appears to us even more important. The body weight curves of our test animals. This correlation, survival time of the tumor-bearing animals increases signifi however, is disguised by the anabolic effect of drostanolone

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*— — —n : control

* V = drostanolone propionate

0 0 = CG 603 0.25'!.

S •= CG 603 0.25'!. + drostanoLone propionate

i

survival days Chart 1. Test A. Survival times of rats bearing DMBA-induced tumors in response to treatment with drostanolone propionate, CG 603, and a combination of these. @ 0- - - -.0=drostanolonepropionate a control S .=CG603 0.25'!., cont. +drostanolone propionate

.——.0 CG 603 0.25'!. •at intervals

+ drostanolone propionate o—o=CGSO3 0.1'!..cont. +drostanolone propionate

Sn I- IF >

‘I

Sn

survival days Chart 2. Test B. Survivaltimes of rats bearing DMBA-inducedtumors in response to combined treatment with drostanolone propionate and CG 603 (pretreatment with drostanolone propionate) in comparison to response to treatment with drostanolone propionate alone.

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Table5

Average life-span calculated on various rates ofs@irvivalofrats bearing DMBA-induced tumors in response to combined treatment with drostanolone propionate and CG 603 (pretreatment with drostanolone propionate) in comparison to treatment with drostanolone pmpionate alone days (mean ±S.E.) @ CompoundSurvivorspropionateaControl5078.63 (%)Survival ±1pcontrolaPdrostanolone 4.68Drostanolone ± propionate, 4.20<0.35CG1 mg 3 times/wk s.c.81.60 ± continually+603, 0.25% drostanolone propionate, 13.37<0.0005<0.0005CG1 mg 3 times/wk s.c.154.10 ± intervals+603, 0.25% at drostanolone propionate, 15.06<0.0005<0.0005CG1 mg 3 times/wk s.c.150.10 ± continually+603, 0.1% drostanolone propionate lmg3times/wks.C.118.10±10.11<0.0025<0.0025Control2598.46± 8.12Drostanolone propionate, 12.40<0.20CG1 mg 3 times/wk s.c.112.27 ± continually+603, 0.25% drostanolone propionate, 12.41<0.0005<0.0005CG1 mg 3 times/wk s.c.177.40 ± intervals+603, 0.25% at drostanolone propionate, 13.56<0.0005<0.0005CG1 mg 3 times/wk s.c.174.73 ± continually+603, 0.1% propionate,1drostanolone 10.79<0.005<0.01Control0119.12±11.76Drostanolonemg 3 times/wk s.c.140.20 ±

propionate, 14.42<0.15CG1 mg 3 times/wk s.c.140.20 ± continually+603,0.25% drostanolone propionate, 10.32<0.0005<0.005CG1 mg 3 times/wk s.c.189.00 ± intervals+603, 0.25 at propionate,1drostanolone 11.20<0.0005<0.01CGmg 3 times/wk s.c.187.05 ± continually+603, 0.1% drostanolone propionate, 1 mg 3times/wks.c.160.15 ±11.32<0.01<0.15

Table6 %changein (a)grossbody weightand (b) net body weight in TestA (g)0 weight interrupted16 CompoundBodywkControla:255.3+4.0+ wk2 wk4 wk6 wk8 wkTreatmentwk10wk12wk14 wk18 wk20 wk22

+12.5+11.1+16.0+15.0+22.6+31.9(untreated)b:252.1+2.4—3.2+ 6.5+ 5.4+10.0

3.7Drostanolonepropionate,a:265.3+6.6+11.5+16.8+21.2+17.6 0.9— 0.6— 4.3+ 2.5 — 0.5— 8.3— 2.4— 17.9— 6.7—

+23.4+22.4+23.5+20.1+35.5+29.6lmg3times/wks.c.b:262.1+6.3+11.2+16.5+18.4+15.2 +19.3+19.3+18.7+13.3+20.6+14.9CG

603, 0.25% pelletsa: 0.8 2.6 3.5 7.9 +10.8 5.0

+10.4CG603,0.25%pelletsa:256.9+7.4+11.6+13.8+12.7+23.8b:254.0250.9±0—1.2+— 1.3+ ±0+ + 0.8+ + 1.4 + 0.5+14.0— 4.1+ — 6.4+20.6 + 0.6+28.6 — 7.6+15.3 +23.0+23.2+18.7+21.0+23.9+28.8+ propionate,lmg3times/wks.c.b:253.7+8.3+12.8+11.4+14.0+25.2drostanelone +23.9+22.8+18.4+21.2+23.2+254

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Table 7

%Change in (a) gross body weight and (b) net body weight in Test B

(g)8wk7'ieatment weight Interruptedl6wkl8wk2Owk22wk24wk26wk28wklOwkl2wkl4wkControla: CompoundBody

9.8

10.7Drostanolonepropionate, b:298.5267.9+4.7 —5.1+10.5— 3.1+17.4 + 2.3+10.9 + 0.1+24.0 + 0.4+35.0 — 8.1+44.5 —16.3+3.9—0.6+ —8.8+24.2—

1.7 0.8 5.6

2.9CG603,0.25%lmg3times/wks.C.a: b:299.2298.4±0 i@1- + 1.9— — 1.4+ 1- 4.2+12.3+ 9.1+10.0 + 4.3+11.3— 0.8+9.7 +1.4+20.3+ 6.4+25.4 +

0 0.9 0.3 1.6 3.4 5.3 8.4 continually

2.2CG603,0.25%+drostanolonepropionate, b:313.7312.8—2.6—2.5±±03.3 — 3.3+ + 0.8+ + 0.2+ + 0.9+ + 1.6+6.1 +1.5+ + 1.4+ + 1 mg 3 times/wk s.c.a:

1.7 3.3 1.0 0.8 0 5.9 atintervals

3.5CG603,0.1%+drostanolonepropionate, b:313.0312.1—4.0—3.9—— 1.9+ + 2.5+ ±0+ — 1.9+10.0 + 4.6± —3.4+7.4+1.9+14.8+ 6.6+ + 1 mg 3 times/wk S.C.a:

3.4 0.5 2.0 4.4 7.2 5.9 continually + drostanolone propionate, b:306.1305.2—1.3—1.2—— 3.6+ — 0.9+ — 1 .5+ — 1 .0+ + S .6+ + 3.2+6.1 +1.1+5.2±0+11.3+ 4.7 1 mg_3_times/wk_s.c.a: in the test groups, i.e., there are tumor-bearing animals in bility of increased predisposition towards infections. From which net weight inéreases under the treatment with further investigations we know that other androgen-active drostanolone although new tumors are developing, or the steroids in combinations with CG 603 are effective against animals even die before the end of the trial. DMBA-induced tumors qualitatively similar but quantita It is generally accepted that a reduction of tumors in size tively different. We have found more cyclic imides which and number is not necessarily connected with an increase of increase the antitumor activity of drostanolone propionate in the survival rate of the tumor-bearing animals. Whether a the rat to a varying degree. This may be important because prolongation of life together with a relative feeling of we know from comparative investigations in the field of well-being can actually be reached in human patients by immunosuppression and leprosy that the cyclic imides can therapeutic procedures has been discussed repeatedly in the act very differently in rats and humans, respectively. We last years. It is with this aspect in mind that we tried to find think that this is due to the various “receptors―specificto out in rats with DMBA-induced tumors whether a prolongs each species. For clinical testing this could mean that the tion of survival time as well as a reduction of the number of investigator must search from among several cyclic imides tumors can be achieved by the combined therapy described tested in animal experiments for the cyclic imide best suited by us. Our results show a decrease of the number of growths for the human patient. in parallel to a considerable prolongation of life . It remains to be seen whether this correlation wifi also be observed in humans treated along the same line. ACKNOWLEDGMENTS The clinical investigations which have now been started will We are obliged to Professor M. Staemmler, Head of the Department show whether these findings from animal experiments can be of Pathology, for performing the postmortems. reproduced in humans. Clinical investigations should show whether the pneumonia occurring as the predominant cause of death in the above experiments can be prevented by REFERENCES antibiotics should it occur in human patients. Regarding the pneumonia in our tumor-bearing animals, 1. Ellenrieder, M., Frankus, E., and Kriipe, W. Immunosuppression this kind of pathological change was found in the untreated durch cyclische Imide bei der Ratte. Kim. Wochschr., 45: controls as well as in the treated groups. Therefore, the 1159—1160,1967. conclusion seems justified that this type of fmal pneumonia 2. Horton, J., Olson, K. B., Cunningham, T., and Sullivan, J. Comparison of a Combination of 5-Fluorouracil (NSC-19893), was part of the tumor disease and was not caused by the Mitomycin C (NSC-26980), Triathyianethiophosphoramide treatment with the compounds. (NSC-6396), and Fluoxymesterone (NSC-12165) with Finally , the immunosuppressive effect (1) of CG 603 in 5-Fluorouracil Alone in Patients with Advanced Cancer. Cancer animal experiments (Sprague-Dawley rats) is not increased by Chemotherapy Rept., 52: 597—599,1968. the addition of drostanolone propionate in doses used in the 3. M@ickter,H.,Frankus, E., and Mor@,E. Experimental Therapeutic tumor trials. This is important when considering the possi Investigations with l.(Morpholinomethyl)4-phthalimido-piperi

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H. Mückter, E. Frankus and E. Moré

Cancer Res 1970;30:430-438.

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