Inhibition of human experimental prostate cancers by a targeted cytotoxic luteinizing hormone-releasing hormone analog AN-207.
BACKGROUND
Receptors for luteinizing hormone-releasing hormone (LHRH) on human prostate cancers can be used for targeted chemotherapy with cytotoxic analogs of LHRH, such as AN-207, which consists of superactive doxorubicin derivative 2-pyrrolino doxorubicin (AN-201) linked to carrier [D-Lys6] LHRH.


METHODS
The effects of AN-207 and AN-201 were investigated in DU-145 androgen independent and LuCaP-35 androgen sensitive human prostate cancers xenografted into nude mice. Toxicity was evaluated by survival rates, changes in body weights, and leukocyte counts. LHRH receptors on DU-145 and LuCaP-35 tumors were evaluated by radioreceptor assays and RT-PCR. The effects on apoptosis and cell proliferation were investigated by histology and evaluation of apoptotic oncogenes Bcl-2 and Bax by Western Blot analysis.


RESULTS
AN-207 inhibited growth of DU-145 tumors significantly by 75% (P < 0.01) and LuCaP-35 human prostate cancers by 80% (P < 0.01), and was less toxic than AN-201. Receptors for LHRH were expressed on DU-145 and LuCaP-35 tumors. Blockade of LHRH receptors with LHRH agonist Triptorelin nullified the effects of AN-207. Treatment with AN-207, but not with AN-201, decreased Bcl-2/Bax ratio in DU-145 tumors and Bcl-2 in LuCaP-35 tumors indicating an increase in apoptotic activity. AN-207, but not AN-201, decreased cell proliferation in both models.


CONCLUSIONS
Targeted chemotherapy with AN-207 could be considered for treatment of advanced prostate cancer.
Stangelberger
Anton
A
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, Louisiana 70112-1262, USA.
Schally
Andrew V
AV
Nagy
Attila
A
Szepeshazi
Karoly
K
Kanashiro
Celia A
CA
Halmos
Gabor
G
D000728:Androgens / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018450:Disease Progression; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000032:analysis; D011966:Receptors, LHRH / Q000378:metabolism; D014183:Transplantation, Heterologous; D017329:Triptorelin Pamoate / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000032:analysis
D000728:Androgens; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D012333:RNA, Messenger; D011966:Receptors, LHRH; D051028:bcl-2-Associated X Protein; D017329:Triptorelin Pamoate; C098751:AN 204; C104648:AN 207; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin