Antitumor effects of the cytotoxic luteinizing hormone-releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice

Carsten Gründker, Peter Völker, Frank Griesinger, Annette Ramaswamy, Attila Nagy, Andrew V Schally, Günter Emons

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

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. STUDY DESIGN: 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. CONCLUSION: 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.

Original languageEnglish
Pages (from-to)528-537
Number of pages10
JournalAmerican Journal of Obstetrics and Gynecology
Volume187
Issue number3
DOIs
StatePublished - Sep 1 2002
Externally publishedYes

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LHRH Receptors
Endometrial Neoplasms
Nude Mice
Gonadotropin-Releasing Hormone
Ovarian Neoplasms
Doxorubicin
Neoplasms
Poisons
Hematopoietic Stem Cells
Tumor Burden
Drug Therapy
Radioligand Assay
Fallopian Tubes
lysine(6)-doxorubicin LHRH
Myometrium
Endometrium
Reverse Transcriptase Polymerase Chain Reaction
Sodium Chloride
Cervix Uteri
Ovary

Keywords

  • AN-152
  • Cytotoxic LHRH analog
  • Endometrial cancer
  • LHRH receptor
  • Ovarian cancer

ASJC Scopus subject areas

  • Medicine(all)
  • Obstetrics and Gynecology

Cite this

Antitumor effects of the cytotoxic luteinizing hormone-releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice. / Gründker, Carsten; Völker, Peter; Griesinger, Frank; Ramaswamy, Annette; Nagy, Attila; Schally, Andrew V; Emons, Günter.

In: American Journal of Obstetrics and Gynecology, Vol. 187, No. 3, 01.09.2002, p. 528-537.

Research output: Contribution to journalArticle

Gründker, Carsten ; Völker, Peter ; Griesinger, Frank ; Ramaswamy, Annette ; Nagy, Attila ; Schally, Andrew V ; Emons, Günter. / Antitumor effects of the cytotoxic luteinizing hormone-releasing hormone analog AN-152 on human endometrial and ovarian cancers xenografted into nude mice. In: American Journal of Obstetrics and Gynecology. 2002 ; Vol. 187, No. 3. pp. 528-537.
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N2 - 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. STUDY DESIGN: 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. CONCLUSION: 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.

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