Clinical and mechanistic aspects of glucocorticoid-induced chemotherapy resistance in the majority of solid tumors.
BACKGROUND
Glucocorticoids have been used widely in conjunction with cancer therapy due to their ability to induce apoptosis in hematological cells and to prevent nausea and emesis. However, recent data including ours, suggest induction of therapy-resistance by glucocorticoids in solid tumors, although it is unclear whether this happens only in few carcinomas or is a more common cell type specific phenomenon.


METHODS
We performed an overall statistical analysis of our new and recent data with 157 tumor probes evaluated in vitro, ex vivo and in vivo. The effect of glucocorticoids on apoptosis, viability and cell cycle progression under diverse clinically important questions was examined.


RESULTS
New in vivo results demonstrate glucocorticoid-induced chemotherapy resistance in xenografted prostate cancer. In an overall statistical analysis we found glucocorticoid-induced resistance in 89% of 157 analysed tumor samples. Resistance is common for several cytotoxic treatments and for several glucocorticoid-derivatives and due to an inhibition of apoptosis, promotion of viability and cell cycle progression. Resistance occurred at clinically achievable peak plasma levels of patients under anti-emetic glucocorticoid therapy and below, lasted for a long time, after one single dose, but was reversible upon removal of glucocorticoids. Two nonsteroidal alternative anti-emetic agents did not counteract anticancer treatment and may be sufficient to replace glucocorticoids in cotreatment of carcinoma patients.


CONCLUSIONS
These data demonstrate the need for prospective clinical studies as well as for detailed mechanistic studies of GC-induced cell-type specific pro- and anti-apoptotic signalling.
Zhang
Chengwen
C
Research Group Molecular OncoSurgery, University of Heidelberg, Im Neuenheimer Feld 365, Heidelberg 69120, Germany.
Wenger
Till
T
Mattern
Jürgen
J
Ilea
Septimia
S
Frey
Christian
C
Gutwein
Paul
P
Altevogt
Peter
P
Bodenmüller
Wolfram
W
Gassler
Nikolaus
N
Schnabel
Philipp A
PA
Dienemann
Hendrik
H
Marmé
Alexander
A
Hohenfellner
Markus
M
Haferkamp
Axel
A
Pfitzenmaier
Jesco
J
Gröne
Hermann-Josef
HJ
Kolb
Armin
A
Büchler
Peter
P
Büchler
Markus
M
Friess
Helmut
H
Rittgen
Werner
W
Edler
Lutz
L
Debatin
Klaus-Michael
KM
Krammer
Peter H
PH
Rutz
Hans P
HP
Herr
Ingrid
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D020360:Neoadjuvant Therapy
D005938:Glucocorticoids