Antitumor effects of the cytotoxic luteinizing hormone-releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice.
OBJECTIVE
Most human endometrial and ovarian cancers express receptors for luteinizing hormone- releasing hormone. These receptors can be used for targeted chemotherapy with cytotoxic luteinizing hormone-releasing hormone analogs such as AN-152, in which doxorubicin is linked to [D-Lys(6)]luteinizing hormone-releasing hormone.


METHODS
The antitumor effects of doxorubicin and AN-152 were assessed in vivo in human luteinizing hormone-releasing hormone receptor-positive HEC-1B endometrial cancers and NIH:OVCAR-3 ovarian cancers and in the luteinizing hormone-releasing hormone receptor-negative SK-OV-3 ovarian line. Nude mice bearing these tumors subcutaneously were injected intravenously with saline solution (control), AN-152, or doxorubicin at equimolar doses. Luteinizing hormone-releasing hormone receptor expression in tumors and specimens of human reproductive (n = 5) and nonreproductive (n = 15) normal tissues and in hematopoietic stem cells were analyzed with reverse transcriptase-polymerase chain reaction and radioligand binding assay.


RESULTS
The tumor volumes of luteinizing hormone-releasing hormone receptor-positive HEC-1B and NIH:OVCAR-3 cancers were reduced significantly (P <.001) 1 week after treatment with AN-152 at 700 nmol/20 g or at 300 nmol/20 g. No toxic side effects were observed. Treatment with doxorubicin arrested tumor growth but did not reduce tumor volume. Doxorubicin at 700 nmol/20 g caused a high mortality rate and at 300 nmol/20 g (8.7 mg/kg) caused a loss of body weight, but no deaths occurred. The growth of luteinizing hormone-releasing hormone receptor-negative SK-OV-3 cancers was not affected by AN-152. Normal human nonreproductive tissues, hematopoietic stem cells, and vaginal tissue did not express luteinizing hormone-releasing hormone receptors, but luteinizing hormone-releasing hormone receptors were found in the ovary, fallopian tube, cervix, endometrium, and myometrium.


CONCLUSIONS
Targeted chemotherapeutic luteinizing hormone-releasing hormone analog AN-152 is more effective and less toxic than cytotoxic radical doxorubicin on luteinizing hormone-releasing hormone receptor-positive tumors. AN-152 could be considered for targeted chemotherapy in patients with ovarian or endometrial cancers.
Gründker
Carsten
C
Departments of Gynecology and Obstetrics, Georg-August-University, Göttingen, Germany.
Völker
Peter
P
Griesinger
Frank
F
Ramaswamy
Annette
A
Nagy
Attila
A
Schally
Andrew V
AV
Emons
Günter
G
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001665:Binding Sites; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000378:metabolism / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011966:Receptors, LHRH / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D011966:Receptors, LHRH; C080883:LHRH, lysine(6)-doxorubicin; D007987:Gonadotropin-Releasing Hormone; D004317:Doxorubicin