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Steroidhormone-receptors and EGF-receptors in endometrial cancer
SOCIETY OF GYNECOLOGIC several drugs, including VP-16 or m-AMSA and cis-DDP, are now being employed because of limited efficacy of single alkylating agents. Clinical trials using drug combinations which have been selected based on sound evidence of drug synergy at a cellular level have not been reported. Therefore, we investigated the mode of scion of VP-16, mAMSA, and cis-DDP at cellular level with a particular emphasis on their effect on enzymes of DNA biosynthesis. VP-16 and m-AMSA are known to induce such DNA damage by interfering with DNA topoisomerase II activity in variety of mammalian cells. In addition, we observed that these anticancer agents inhibited thymidylate synthase (TS) activity when measured in intact Chinese hamster embryo fibroblast (CHEF/l@ or ovary (CHO) cells. This inhibition of TS activity was parallel to that of DNA synthesis. An analysis of the intracellular deoxynucleotide pools and the examination of the enzymes associated with DNA biosynthesis indicated that the observed inhibition of TS activity in intact cells by VP-16 or m-AMSA is due to the allosteric interaction of TS with the target enzyme of these anticancer drugs, viz., DNA topoisomerase II. By contrast, cis-DDP, that is also known to produce DNA lesions, did not have any inhibitory effect on TS or DNA topoisomerase II activities. These studies suggest that the mechanism by which VP-16 or m-AMSA exert anticancer effect is different from that exerted by cis-DDP. Therefore, a combination of VP-16 or m-AMSA with cis-DDP should have a synergistic anticancer effect. This prediction is currently being tested through cell survival studies.
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method (DCC). Tissue was receptor positive at 50 fmole/mg or more protein. In addition, in 60 cases EGF-receptors (EGF-R) were determined by biochemical methods. These results were correlated to anamnestical and clinical data and clinical course as age, stage, histological type, and differentiation as well as survival time according to follow-up to 9 years. Sixty-eight percent of endometrial cancer was ER and/or PR positive. Related to anamnestical data (age, menarche, menopause) no difference was seen between receptor-positive and negative patients. There was a good correlation to other prognostic factors in endometrial cancer such as stage, grade of histological differentiation, and myometrial invasion. Multivariance analysis demonstrated the PR as the most important prognostic factor in endometrial cancer. Sixty cases with EGF-R analysis also showed an inverse correlation: most of the steroid receptor-positive cases were EGF-R-negative and vice versa. According to this first result, endometrial cancer with a high EGF-R concentration seems to be correlated with a poor prognosis. 29. Prognostic Relevance of Flowcytophotometric Studies in Ovarian *DKFZ, Carcinoma. W. KLEINE, M. VOLM,* AND A. PFLEIDERER. D-6900 Heidelberg, and University of Frauenklinik, D-7800 Freiburg, Federal Republic of Germany.
The prognostic significance of DNA content and of distribution of cell cycle phases in ovarian carcinomas (stages III and IV) was investigated using flow cytometry. From 37 tumors, 15 had DNA indices 21. Uterine Cervix Cancer Treatment Complications: Preliminary Results <2.5 and 22 had DNA indices >2.5 (diploid, 2). Patients with diploid of a Multicentric Study. P. SISMONDI, P. ZOLA, AND G. SINISTRERO, or near diploid tumors had significantly longer survival times than those in collaboration with Study Participants. Department of Gynecology, with aneuploid tumors (DNA indices >2.5) (log-rank test, P = 0.009; University of Torino, and Italian National Research Council, Special rank-sum test, P = 0.011). Patients whose tumors showed a high Project Oncology, Via Ventimiglia, 3; 10126Torino, Italy. proportion of S/G/M-phase cells (>17%) had shorter survival times than those with tumors with a lower proportion of S/G/M-phase cells A patient bearing a uterine cervix cancer at given stages, can be (log-rank test, P = 0.009, rank-sum test, P = 0.022). The median treated in different ways that are assumed to give similar results. A length of follow-up of the patients was 5 years. Thus, our experiments possible approach to help choose among the different treatments could be the analysis of the cost-to-benefit ratio, but published data on have shown that measurements of DNA ploidy and proliferative activity complications cannot be compared. Eight years ago we wrote a glossary using flow cytometry are important prognostic indicators for patients with ovarian carcinomas. In the future, these factors might play an encompassing most of the sequelae and complications of the different important role for the prognosis of patients with ovarian carcinomas. therapeutic modalities and tested its applicability in a small number of Institutions. In 1983 we invited 19 institutions to participate in a co- In addition, there exists a tendency for patients with in vitro resistant operative study aimed at comparing treatment results and complications. tumors to die earlier than those with sensitive tumors, but these results Each institution agreed to classify patients according to UICC and were not significant (log-rank test, P = 0.16; rank-sum tests, P = FIG0 rules, to perform treatment according to its own treatment protocol, 0.059). to adhere to a uniform follow-up schedule and to record complications according to the glossary. A quality assurance program was set up in 30. Pilot Study of High-Dose Chemoradiotherapy with Autologous Bone order to reduce the inter- and intracenter variability. A total of 2663 Marrow Rescue (ABMR) for Persistent Ovarian Cancer. J. CAIN, patients have been registered by June 30, 1988, and 98 different comC. COLLINS, W. J. KOH, W. PETERSIII, ANDH. K. TAMIMI,University plications have been observed. Frequency, probability, onset time, of Washington and Puget Sound Oncology Consortium, Seattle, associations, treatments, healing time, and probability of the most Washington 98195. frequently observed complications have been studied. The life-table Based on experience with high-dose chemoradiotherapy and ABMT method has been used to evaluate the probability of complication as well as survival (SUR) and disease-free survival (DFS). Among the in the treatment of refractory solid tumors, a pilot study of Cytoxan 1301patients at the stages Tlb-T2a, we selected three groups of patients (60 mg/kg x 2) 2 cisplatin (100 mg/m*); thoracoahdominal radiation who received different treatments only because of the different treatment (800 cGy X I), and ABMR was begun in September 1987.Nine patients policies of the referral institutions. SUR, DFS, and complications prob- have completed evaluation for inclusion. Five were ineligible. Two had abilities have been compared; no differences were found for SUR and low left ventricular ejection fractions (LVEF); one of these is dead of DFS, but the pattern and probability of complications show some disease and the second has progressive disease. Three were found to interesting differences. A randomized trial could be warranted if the have positive bone marrow aspirates (3+ by immunocytochemistry, 1 of the 3+ also by microscopy.) Two received high dose Cytoxan: observed differences remain after a longer follow-up. one is free of disease at 7 months (- bone marrow) and one is too early to evaluate. The third patient has progressive disease. Four patients 28. Steroidhormone-Receptors and EGF-Receptors in Endometrial Cancer. W. KLEINE, H. GEYER,TH. BAUKNECHT,AND A. PFLEIDERER, completed the protocol. One died 5 days post-transplant with right University of Frauenklinik, D-7806 Freiburg, Federal Republic of ventricular failure. Autopsy showed an adriamycin-related cardiomyopathy. Two had declining CA-125 levels 2 and 4 months post-treatment Germany. when the levels began to rise, although both are clinically free of Estrogen (ER) and progesterone receptors (PR) were determined in disease. One patient remains free of disease 2 months following treatment. endometrial cancer tissue of 300 patients by the dextran-coated charcoal This experience will be updated, but raises two concerns. First, the
ONCOLOGISTS-ABSTRACTS
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method (DCC). Tissue was receptor positive at 50 fmole/mg or more protein. In addition, in 60 cases EGF-receptors (EGF-R) were determined by biochemical methods. These results were correlated to anamnestical and clinical data and clinical course as age, stage, histological type, and differentiation as well as survival time according to follow-up to 9 years. Sixty-eight percent of endometrial cancer was ER and/or PR positive. Related to anamnestical data (age, menarche, menopause) no difference was seen between receptor-positive and negative patients. There was a good correlation to other prognostic factors in endometrial cancer such as stage, grade of histological differentiation, and myometrial invasion. Multivariance analysis demonstrated the PR as the most important prognostic factor in endometrial cancer. Sixty cases with EGF-R analysis also showed an inverse correlation: most of the steroid receptor-positive cases were EGF-R-negative and vice versa. According to this first result, endometrial cancer with a high EGF-R concentration seems to be correlated with a poor prognosis. 29. Prognostic Relevance of Flowcytophotometric Studies in Ovarian *DKFZ, Carcinoma. W. KLEINE, M. VOLM,* AND A. PFLEIDERER. D-6900 Heidelberg, and University of Frauenklinik, D-7800 Freiburg, Federal Republic of Germany.
The prognostic significance of DNA content and of distribution of cell cycle phases in ovarian carcinomas (stages III and IV) was investigated using flow cytometry. From 37 tumors, 15 had DNA indices 21. Uterine Cervix Cancer Treatment Complications: Preliminary Results <2.5 and 22 had DNA indices >2.5 (diploid, 2). Patients with diploid of a Multicentric Study. P. SISMONDI, P. ZOLA, AND G. SINISTRERO, or near diploid tumors had significantly longer survival times than those in collaboration with Study Participants. Department of Gynecology, with aneuploid tumors (DNA indices >2.5) (log-rank test, P = 0.009; University of Torino, and Italian National Research Council, Special rank-sum test, P = 0.011). Patients whose tumors showed a high Project Oncology, Via Ventimiglia, 3; 10126Torino, Italy. proportion of S/G/M-phase cells (>17%) had shorter survival times than those with tumors with a lower proportion of S/G/M-phase cells A patient bearing a uterine cervix cancer at given stages, can be (log-rank test, P = 0.009, rank-sum test, P = 0.022). The median treated in different ways that are assumed to give similar results. A length of follow-up of the patients was 5 years. Thus, our experiments possible approach to help choose among the different treatments could be the analysis of the cost-to-benefit ratio, but published data on have shown that measurements of DNA ploidy and proliferative activity complications cannot be compared. Eight years ago we wrote a glossary using flow cytometry are important prognostic indicators for patients with ovarian carcinomas. In the future, these factors might play an encompassing most of the sequelae and complications of the different important role for the prognosis of patients with ovarian carcinomas. therapeutic modalities and tested its applicability in a small number of Institutions. In 1983 we invited 19 institutions to participate in a co- In addition, there exists a tendency for patients with in vitro resistant operative study aimed at comparing treatment results and complications. tumors to die earlier than those with sensitive tumors, but these results Each institution agreed to classify patients according to UICC and were not significant (log-rank test, P = 0.16; rank-sum tests, P = FIG0 rules, to perform treatment according to its own treatment protocol, 0.059). to adhere to a uniform follow-up schedule and to record complications according to the glossary. A quality assurance program was set up in 30. Pilot Study of High-Dose Chemoradiotherapy with Autologous Bone order to reduce the inter- and intracenter variability. A total of 2663 Marrow Rescue (ABMR) for Persistent Ovarian Cancer. J. CAIN, patients have been registered by June 30, 1988, and 98 different comC. COLLINS, W. J. KOH, W. PETERSIII, ANDH. K. TAMIMI,University plications have been observed. Frequency, probability, onset time, of Washington and Puget Sound Oncology Consortium, Seattle, associations, treatments, healing time, and probability of the most Washington 98195. frequently observed complications have been studied. The life-table Based on experience with high-dose chemoradiotherapy and ABMT method has been used to evaluate the probability of complication as well as survival (SUR) and disease-free survival (DFS). Among the in the treatment of refractory solid tumors, a pilot study of Cytoxan 1301patients at the stages Tlb-T2a, we selected three groups of patients (60 mg/kg x 2) 2 cisplatin (100 mg/m*); thoracoahdominal radiation who received different treatments only because of the different treatment (800 cGy X I), and ABMR was begun in September 1987.Nine patients policies of the referral institutions. SUR, DFS, and complications prob- have completed evaluation for inclusion. Five were ineligible. Two had abilities have been compared; no differences were found for SUR and low left ventricular ejection fractions (LVEF); one of these is dead of DFS, but the pattern and probability of complications show some disease and the second has progressive disease. Three were found to interesting differences. A randomized trial could be warranted if the have positive bone marrow aspirates (3+ by immunocytochemistry, 1 of the 3+ also by microscopy.) Two received high dose Cytoxan: observed differences remain after a longer follow-up. one is free of disease at 7 months (- bone marrow) and one is too early to evaluate. The third patient has progressive disease. Four patients 28. Steroidhormone-Receptors and EGF-Receptors in Endometrial Cancer. W. KLEINE, H. GEYER,TH. BAUKNECHT,AND A. PFLEIDERER, completed the protocol. One died 5 days post-transplant with right University of Frauenklinik, D-7806 Freiburg, Federal Republic of ventricular failure. Autopsy showed an adriamycin-related cardiomyopathy. Two had declining CA-125 levels 2 and 4 months post-treatment Germany. when the levels began to rise, although both are clinically free of Estrogen (ER) and progesterone receptors (PR) were determined in disease. One patient remains free of disease 2 months following treatment. endometrial cancer tissue of 300 patients by the dextran-coated charcoal This experience will be updated, but raises two concerns. First, the