In vitro cytotoxic effects of imatinib in combination with anticancer drugs in human prostate cancer cell lines.
BACKGROUND
The platelet-derived growth factor receptor (PDFG-r), a tyrosine kinase, is expressed in 88% of primary prostate cancer and in 80% of the metastases. The tyrosine kinase inhibitor imatinib blocks the PDGF signaling pathway by inhibiting PDGF-r autophosphorylation. We examined the cytotoxic effects of imatinib in combination with other anticancer agents in the human prostate cancer cell lines LNCaP, PC-3, and DU 145.


METHODS
The cells were exposed to imatinib and to the other drugs simultaneously for 5 days. Cell growth inhibition was determined by XTT assay. The cytotoxic effects in combinations were evaluated at the inhibitory concentration of 50% level by the isobologram.


RESULTS
Imatinib produced additive effects with estramustine phosphate (EMP) and 4-hydroperoxy-cyclophosphamide in all three cell lines. In combination with etoposide imatinib produced additive effects in two of three cell lines. Imatinib with docetaxel produced antagonistic effects in PC-3 and additive to antagonistic effects in LNCaP and DU 145 cells.


CONCLUSIONS
The simultaneous exposure of imatinib and EMP would be effective against hormone sensitive and hormone insensitive cell lines and this combination should be evaluated in clinical trials. In contrast, the simultaneous exposure of imatinib and docetaxel would have little therapeutic efficacy. Although there are gaps between in vitro studies and clinical trials, the present findings provide useful information for the establishment of clinical protocols involving imatinib in hormone-refractory prostate cancer.
Kübler
Hubert R
HR
Department of Urology, Klinikum rechts der Isar, Technical University Munich, Germany. h.kuebler@lrz.tum.de
van Randenborgh
Heiner
H
Treiber
Uwe
U
Wutzler
Sebastian
S
Battistel
Carolus
C
Lehmer
Antonie
A
Wagenpfeil
Stefan
S
Hartung
Rudolf
R
Paul
Roger
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077143:Docetaxel; D004357:Drug Synergism; D004961:Estramustine / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology
C093853:4-hydroxyperoxycyclophosphamide; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D043823:Taxoids; D000077143:Docetaxel; D004961:Estramustine; D005047:Etoposide; D000068877:Imatinib Mesylate; D003520:Cyclophosphamide; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor