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.
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.
Kristensen
C A
CA
Finsen Center, National University Hospital, University of Copenhagen, Denmark.
Kristjansen
P E
PE
Brünner
N
N
Quistorff
B
B
Spang-Thomsen
M
M
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
D010710:Phosphates; D013629:Tamoxifen; D003402:Creatine Kinase