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[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. 430 CANCER RESEARCH VOL.30 Downloaded from cancerres.aacrjournals.org on September 23, 2021. © 1970 American Association for Cancer Research. CG 603 and Drostanolone Propionate in DMBA-induced Tumors 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 FEBRUARY 1970 431 Downloaded from cancerres.aacrjournals.org on September 23, 2021.

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