Abstract
Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS-108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers.
| Original language | English |
|---|---|
| Pages (from-to) | 686-699 |
| Number of pages | 14 |
| Journal | Oncotarget |
| Volume | 3 |
| Issue number | 7 |
| Publication status | Published - júl. 2012 |
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ASJC Scopus subject areas
- Oncology
Cite this
Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108). / Szepeshazi, Karoly; Schally, Andrew V.; Keller, Gunhild; Block, Norman L.; Benten, Daniel; Halmos, Gabor; Szalontay, Luca; Vidaurre, Irving; Jászberényi, M.; Rick, Ferenc G.
In: Oncotarget, Vol. 3, No. 7, 07.2012, p. 686-699.Research output: Article
}
TY - JOUR
T1 - Receptor-targeted therapy of human experimental urinary bladder cancers with cytotoxic LH-RH analog AN-152 (AEZS-108)
AU - Szepeshazi, Karoly
AU - Schally, Andrew V.
AU - Keller, Gunhild
AU - Block, Norman L.
AU - Benten, Daniel
AU - Halmos, Gabor
AU - Szalontay, Luca
AU - Vidaurre, Irving
AU - Jászberényi, M.
AU - Rick, Ferenc G.
PY - 2012/7
Y1 - 2012/7
N2 - Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS-108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers.
AB - Many bladder cancers progress to invasion with poor prognosis; new therapeutic methods are needed. We developed a cytotoxic LH-RH analog, AN-152 (AEZS-108) containing doxorubicin (DOX), for targeted therapy of cancers expressing LHRH receptors. We investigated the expression of LH-RH receptors in clinical bladder cancers and in HT-1376, J82, RT-4 and HT-1197 human bladder cancer lines. The effect of analog, AN-152, on growth of these tumor lines xenografted into nude mice was analyzed. Using molecular and functional assays, we also evaluated the differences between the effects of AN-152, and DOX alone. We demonstrated the expression of LH-RH receptors on 18 clinical bladder cancers by immunohistochemistry and on four human urinary bladder cancer lines HT-1376, J82, RT-4 and HT-1197 by Western blotting and binding assays. AN-152 powerfully inhibited growth of these bladder cancers in nude mice. AN-152 exerted greater effects than DOX and was less toxic. DOX activated strong multidrug resistance mechanisms in RT-4 and HT-1197 cancers, while AN-152 had no or less such effect. PCR assays and in vitro studies revealed differences in the action of AN-152 and DOX on the expression of genes involved in apoptosis. These results suggest that targeted cytotoxic LH-RH analog, AN-152 (AEZS-108), should be examined for treatment of patients with LH-RH receptor positive invasive bladder cancers.
KW - Cytotoxic
KW - Doxorubicin
KW - LH-RH receptor
KW - Targeted therapy
KW - Urinary bladder
KW - Urothelial cancer
UR - http://www.scopus.com/inward/record.url?scp=84868626417&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84868626417&partnerID=8YFLogxK
M3 - Article
C2 - 22824624
AN - SCOPUS:84868626417
VL - 3
SP - 686
EP - 699
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 7
ER -