Corticosteroid-Induced Chemotherapy Resistance in Urological Cancers.
Entrez PubMed
Cancer Biol Ther. 2006 Jan 25;5(1) [Epub ahead of print]
Corticosteroid-Induced Chemotherapy Resistance in Urological Cancers.
Zhang C, et al. Molecular Urooncology, German Cancer Research Center, Heidelberg, Germany.
Purpose: Glucocorticoids such as dexamethasone are widely used for medication of urological diseases, e.g., as cotreatment of advanced prostate cancer, to improve appetite, weight loss, fatigue, relieve bone pain, diminish ureteric obstruction, to reduce the production of adrenal androgens, as an antiemetic in patients undergoing chemo- and/or radiotherapy together with serving as “standard” therapy arm in randomized studies.
While the potent pro-apoptotic properties and the supportive effects of glucocorticoids to tumor therapy in lymphoid cells are well studied, the impact to growth of prostate and other urological carcinomas is unknown.
Methods: We isolated cells from surgical resections of 21 prostate tumors and measured apoptosis and viability in these primary cells and 17 established cell lines from human prostate, bladder, renal cell and testicular carcinomas.
Results: We found that dexamethasone induces resistance regarding exposure to several cytotoxic agents such as taxol, gemcitabine, cisplatin, 5-FU and gamma-irradiation in 86% of the freshly isolated prostate tumors and in 100% of the established urological cell lines.
No difference in dexamethasone-mediated protection was found in normal, benign and malignant prostate tumors.
Conclusions: These data show for the first time that dexamethasone induced therapy resistance in urological carcinomas is not the exception but a more common phenomenon and implicate that glucocorticoids may have two faces in cancer therapy, a beneficial and a dangerous one.
NOTE from psa-rising editor: This looks like a rather chilling early confirmation of a finding in breast cancer which we were concerned might apply also to prostate cancer. See:
Widely used anti-nausea drug, dexamethasone, may interfere with breast cancer chemotherapy
by J. Strax
Evidence for value of dexamethasone with CALCITRIOL to tx PCa inlcudes, recently:
Entrez PubMed
J Steroid Biochem Mol Biol. 2004 May;89-90(1-5):519-26.
Anti-tumor activity of calcitriol: pre-clinical and clinical studies.
Trump DL, Hershberger PA, Bernardi RJ, Ahmed S, Muindi J, Fakih M, Yu WD, Johnson CS.
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
1,25-Dihydroxycholecalciferol (calcitriol) is recognized widely for its effects on bone and mineral metabolism. Epidemiological data suggest that low Vitamin D levels may play a role in the genesis of prostate cancer and perhaps other tumors. Calcitriol is a potent anti-proliferative agent in a wide variety of malignant cell types. In prostate, breast, colorectal, head/neck and lung cancer as well as lymphoma, leukemia and myeloma model systems calcitriol has significant anti-tumor activity in vitro and in vivo. Calcitriol effects are associated with an increase in G0/G1 arrest, induction of apoptosis and differentiation, modulation of expression of growth factor receptors. Glucocorticoids potentiate the anti-tumor effect of calcitriol and decrease calcitriol-induced hypercalcemia. Calcitriol potentiates the antitumor effects of many cytotoxic agents and inhibits motility and invasiveness of tumor cells and formation of new blood vessels. Phase I and II trials of calcitriol either alone or in combination with carboplatin, taxanes or dexamethasone have been initiated in patients with androgen dependent and independent prostate cancer and advanced cancer. Data indicate that high-dose calcitriol is feasible on an intermittent schedule, no dose-limiting toxicity has been encountered and optimal dose and schedule are being delineated. Clinical responses have been seen with the combination of high dose calcitriol dexamethasone in androgen independent prostate cancer (AIPC) and apparent potentiation of the antitumor effects of docetaxel have been seen in AIPC. These results demonstrate that high intermittent doses of calcitriol can be administered to patients without toxicity, that the MTD is yet to be determined and that calcitriol has potential as an anti-cancer agent.
Thanks to Gordon for this.
Comment by admin — December 22, 2005 @ 1:11 amAn earlier article on dexamethason with Calcitriol is available in full free text in .pdf format
from JNCI Cancer Spectrum 1998
Enhancement of 1,25-dihydroxyvitamin D3-mediated antitumor activity with dexamethasone
WD Yu, MC McElwain, RA Modzelewski, DM Russell, DC Smith, DL Trump and CS Johnson
Department of Otolaryngology, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, PA 15213, USA.
BACKGROUND: The active metabolite of vitamin D, i.e., 1,25- dihydroxycholecalciferol (1,25-D3), inhibits the growth of murine SCCVII/SF squamous cell carcinoma cells, both in vitro and in vivo. However, in vivo use of 1,25-D3 is hampered as a result of hypercalcemia (i.e., elevated levels of calcium in the blood). Glucocorticoids, such as dexamethasone, affect calcium absorption and modulate vitamin D receptor binding and have been used to treat hypercalcemia. In this study, we examined the effect of dexamethasone on tumor growth inhibition by 1,25-D3. METHODS: The effects of 1,25-D3 and dexamethasone, alone and in combination, on the growth of SCCVII/SF cells in in vitro culture or in vivo in female C3H/HeJ mice were determined by clonogenic tumor cell assay and/or by actual changes in tumor volume. Vitamin D receptor-ligand-binding activities in whole- cell extracts from cells (in culture), tumors, and normal tissues were assayed by single-point saturation analysis and equilibrium binding. RESULTS: Treatment of cultured SCCVII/SF cells with 500 nM dexamethasone for 24 hours before addition of 1,25-D3 reduced their survival. The growth of SCCVII/SF tumors was inhibited in mice treated simultaneously with dexamethasone and 1,25-D3 (as compared with no treatment or single-agent treatment); hypercalcemia was also reduced. Total vitamin D receptor content in SCCVII/SF cells was increased after treatment with dexamethasone. Treatment of tumor-bearing animals with dexamethasone (9 microg/day) for 7 days led to increased vitamin D receptor-ligand-binding activities in whole-cell extracts from tumor or kidneys and decreased activity in intestinal mucosa. CONCLUSIONS: Dexamethasone may enhance the antitumor effect of 1,25-D3 by increasing vitamin D receptor-ligand-binding activity.
Comment by admin — December 22, 2005 @ 1:14 am