title: Growth inhibition in response to estrogen withdrawal and tamoxifen therapy of human breast cancer xenografts evaluated by in vivo 31P magnetic resonance spectroscopy, creatine kinase activity, and apoptotic index.
abstract: Estrogen withdrawal versus tamoxifen (TAM) treatment was compared in two human breast cancer xenografts, the estrogen-dependent ZR75-1 and its estrogen-independent subline ZR75/LCC-3. The following parameters were determined: tumor growth, NTP:P(i) by 31P magnetic resonance spectroscopy, apoptotic index, and creatine kinase (CK) activity. Tumors of each line were grown in ovariectomized nude mice during stimulation from a s.c. 17 beta-estradiol pellet. At a tumor size of approximately 350 mm3, the pellet was removed from one-half of the animals. The remaining one-half served as controls. In parallel experiments, injections of TAM were initiated instead of estrogen withdrawal. Estrogen withdrawal as well as TAM induced growth inhibition of ZR75-1 tumors, whereas ZR75/LCC-3 was resistant to both types of therapy. Growth inhibition of ZR75-1 by estrogen withdrawal, but not by TAM, was accompanied by an 80% increase of the NTP:P(i) ratio (P < 0.01) and a significantly decreased cytosolic CK activity (P < 0.01). No significant change in pH was observed. These changes seemed not to be related to changes in apoptotic index. None of the described changes occurred in ZR75/LCC-3. The present data indicate: (a) ZR75-1 and ZR75/LCC-3 xenografts respond differently to estrogen withdrawal and TAM with regard to growth inhibition, 31P magnetic resonance spectroscopy, and CK activity; (b) estrogen withdrawal, but not TAM, induced a decrease in the CK activity of estrogen-dependent tumor tissue, and (c) increased apoptosis did not explain the growth inhibition and the increase in NTP:P(i) induced by estrogen withdrawal. The results indicate other growth inhibitory mechanisms of TAM in addition to competitive inhibition of the estrogen receptor.
authors.affiliation: Finsen Center, National University Hospital, University of Copenhagen, Denmark.
authors.forename: C A
authors.initials: CA
authors.lastname: Kristensen
authors.forename: P E
authors.initials: PE
authors.lastname: Kristjansen
authors.forename: N
authors.initials: N
authors.lastname: Brünner
authors.forename: B
authors.initials: B
authors.lastname: Quistorff
authors.forename: M
authors.initials: M
authors.lastname: Spang-Thomsen
mesh_terms: D000818:Animals; D017209:Apoptosis; D003402:Creatine Kinase / Q000378:metabolism*; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D010052:Ovariectomy; D010710:Phosphates / Q000378:metabolism; D013629:Tamoxifen / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D010710:Phosphates; D013629:Tamoxifen; D003402:Creatine Kinase