leuprolide and Pancreatic-Neoplasms

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leuprolide; Male; Middle Aged; Pancreatic Neoplasms; Tamoxifen

The roles of estrogen receptors (ERs) and the efficacy of anti-estrogen (E2) therapies in pancreatic cancer stay controversial. The main objectives of this study were to investigate the potential roles of ERs in tumor progression and endocrine therapies.. The ER expression status in PANC-1 and SW1990 pancreatic cancer cell lines was determined. SRB assay, colony formation assay and proliferation assay were used to investigate the responses of these cells to E2. ERα-selective agonist propylpyrazoletriol (PPT), ERβ-selective agonist diarylpropionitrile (DPN), ERα over-expressed SW1990 cells, ERα knock-out PANC-1 cells and patient-derived xenografts (PDX) were applied to investigate the potential roles of ERα in pancreatic cancer. The phosphorylation of ERα-related signaling molecules extracellular regulated protein kinases (ERK1/2) and protein kinase B (AKT) were investigated. The in vivo anti-tumor efficacy and safety of letrozole (LTZ) combined with leuprorelin acetate (LA) and gemcitabine (GEM) were also preliminarily studied.. PANC-1 cells expressed much more ERα than SW1990 cells, and ERβ level was with less diversity. Accordingly, the proliferation of PANC-1 rather than SW1990 cells could be stimulated by E2, and only PANC-1 could respond to LTZ endocrine therapy in female but not male mice. The phosphorylation of ERK1/2 but not AKT was altered by over-expressed or knocking out of ERα with or without the addition of E2 and LTZ. The combination therapy of LTZ and GEM showed acceptable efficacy and safety.. This study showed the important roles of ERα in tumor progression and endocrine therapies of pancreatic cancer in women.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Deoxycytidine; Estradiol; Estrogen Receptor alpha; Estrogen Receptor Modulators; Female; Gemcitabine; Gene Expression; Gene Knockout Techniques; Humans; Letrozole; Leuprolide; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Pancreatic Neoplasms; Xenograft Model Antitumor Assays

Estrogen receptor (ER) has been found in human pancreatic carcinoma, but the potential benefit of endocrine therapy never has been assessed adequately. The aim of this study was to determine whether the presence of ER can be used as an indicator of hormone responsiveness, and whether modulation of tissue-type plasminogen activator (t-PA) by ER can identify hormone-responsive pancreatic carcinomas.. The authors investigated ER status and hormonal regulation of t-PA in nine human pancreatic carcinoma cell lines, AsPC-1, BxPC-3, Capan-1, Capan-2, Hs-700T, Hs-766T, MiaPaCa-2, PANC-1, and SUIT-2. Furthermore, to examine whether estrogen dependency of t-PA production in pancreatic carcinoma cells correlated with responsiveness to endocrine therapy, the in vivo effects of various endocrine agents on the growth of the nine pancreatic cell lines transplanted into nude mice were examined.. In a 17 beta-estradiol (E2)-binding assay, three of the nine pancreatic carcinoma cell lines (BxPC-3, Capan-2, and MiaPaCa-2) contained measurable levels of estradiol binding sites in vitro and in vivo using tumors transplanted into nude mice. Although t-PA was present in the culture medium in eight of the nine pancreatic carcinoma cell lines (not in Hs-700T), t-PA production was regulated by estrogen via an ER system in vitro only in the Capan-2 cell line. E2 injection into tumor-bearing mice showed acceleration of tumor growth only in Capan-2 tumors. Administration of a competitive ER antagonist, toremifene, and a luteinizing hormone-releasing hormone analogue, leuprorelin acetate (LEU), to Capan-2-bearing mice significantly reduced the rate of tumor growth, although there was no actual shrinkage of tumor mass. These agents failed to exert any antitumor effect on the other eight pancreatic cell lines. Although aromatase inhibitors, CGS 20267 and vorozole did not modify the in vivo growth of the nine pancreatic carcinoma cell lines significantly, the combined use of aromatase inhibitors with LEU exhibited a synergistic antitumor effect on Capan-2-bearing mice. Medroxyprogesterone acetate treatment significantly reduced the tumor volume of Capan-2 and also caused delayed growth in two other cell lines, AsPC-1 and MiaPaCa-2.. The estrogen dependency of t-PA production may clarify the functional state of ER in human pancreatic carcinoma cells. This finding may aid in planning endocrine therapy for patients with this lethal cancer.

Topics: Animals; Aromatase Inhibitors; Binding Sites; Cycloheximide; Dactinomycin; Drug Screening Assays, Antitumor; Estrogens; Female; Gonadotropin-Releasing Hormone; Humans; Leuprolide; Medroxyprogesterone Acetate; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Hormone-Dependent; Pancreatic Neoplasms; Receptors, Estrogen; Tissue Plasminogen Activator; Toremifene; Tumor Cells, Cultured