Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone- releasing hormone, AN-207

Z. Kahán, Attila Nagy, Andrew V. Schally, Gábor Halmos, José M. Arencibia, Kate Groot

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

BACKGROUND. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast carcinomas. A highly potent cytotoxic agent, 2-pyrrolinodoxorubicin (AN-201), was linked to the agonist [D- Lys6]LH-RH to form a cytotoxic LH-RH analog, AN-207, that can be targeted to LH-RH receptors on breast carcinomas. METHODS. Nude mice bearing MX-1 hormone-independent, doxorubicin-resistant human breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 and [D-Lys6]LH-RH. Tumor growth and changes in hematologic parameters were evaluated. Receptors for LH-RH were investigated by radioreceptor assays, and the expression of their mRNA was determined by reverse transcriptase-polymerase chain reaction. RESULTS. AN-207 caused complete regression of MX-1 tumors in all 10 animals, and they were still tumor free 60 days after treatment. In contrast, after therapy with AN-201 or the mixture of AN-201 and [D-Lys6]LH-RH, the regression of most MX-1 tumors was only transitory. AN-201 caused the death of 1 of the 10 animals and significantly greater leukopenia than AN-207, which produced no toxic deaths. Radioreceptor assays revealed high affinity binding sites for LH-RH on tumor cell membranes. The expression of mRNA for LH-RH receptors also was found in tumors. CONCLUSIONS. The results of this study indicate thai powerful, targeted cytotoxic LH-RH analogs such as AN-207 could be considered for the treatment of human breast carcinomas that possesses receptors for LH-RH.

Original languageEnglish
Pages (from-to)2608-2615
Number of pages8
JournalCancer
Volume85
Issue number12
DOIs
Publication statusPublished - Jun 15 1999

Fingerprint

Heterografts
Gonadotropin-Releasing Hormone
LHRH Receptors
Breast Neoplasms
Drug Therapy
Neoplasms
Radioligand Assay
Messenger RNA
Poisons
Cytotoxins
Leukopenia
AN 204
AN 207
Reverse Transcriptase Polymerase Chain Reaction
Nude Mice
Doxorubicin
Binding Sites
Cell Membrane
Hormones
Therapeutics

Keywords

  • Breast carcinoma
  • Cytotoxic LH-RH analog
  • MX-1 human breast carcinoma xenograft
  • Receptor targeted chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone- releasing hormone, AN-207. / Kahán, Z.; Nagy, Attila; Schally, Andrew V.; Halmos, Gábor; Arencibia, José M.; Groot, Kate.

In: Cancer, Vol. 85, No. 12, 15.06.1999, p. 2608-2615.

Research output: Contribution to journalArticle

Kahán, Z. ; Nagy, Attila ; Schally, Andrew V. ; Halmos, Gábor ; Arencibia, José M. ; Groot, Kate. / Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone- releasing hormone, AN-207. In: Cancer. 1999 ; Vol. 85, No. 12. pp. 2608-2615.
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abstract = "BACKGROUND. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50{\%} of human breast carcinomas. A highly potent cytotoxic agent, 2-pyrrolinodoxorubicin (AN-201), was linked to the agonist [D- Lys6]LH-RH to form a cytotoxic LH-RH analog, AN-207, that can be targeted to LH-RH receptors on breast carcinomas. METHODS. Nude mice bearing MX-1 hormone-independent, doxorubicin-resistant human breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 and [D-Lys6]LH-RH. Tumor growth and changes in hematologic parameters were evaluated. Receptors for LH-RH were investigated by radioreceptor assays, and the expression of their mRNA was determined by reverse transcriptase-polymerase chain reaction. RESULTS. AN-207 caused complete regression of MX-1 tumors in all 10 animals, and they were still tumor free 60 days after treatment. In contrast, after therapy with AN-201 or the mixture of AN-201 and [D-Lys6]LH-RH, the regression of most MX-1 tumors was only transitory. AN-201 caused the death of 1 of the 10 animals and significantly greater leukopenia than AN-207, which produced no toxic deaths. Radioreceptor assays revealed high affinity binding sites for LH-RH on tumor cell membranes. The expression of mRNA for LH-RH receptors also was found in tumors. CONCLUSIONS. The results of this study indicate thai powerful, targeted cytotoxic LH-RH analogs such as AN-207 could be considered for the treatment of human breast carcinomas that possesses receptors for LH-RH.",
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T1 - Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone- releasing hormone, AN-207

AU - Kahán, Z.

AU - Nagy, Attila

AU - Schally, Andrew V.

AU - Halmos, Gábor

AU - Arencibia, José M.

AU - Groot, Kate

PY - 1999/6/15

Y1 - 1999/6/15

N2 - BACKGROUND. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast carcinomas. A highly potent cytotoxic agent, 2-pyrrolinodoxorubicin (AN-201), was linked to the agonist [D- Lys6]LH-RH to form a cytotoxic LH-RH analog, AN-207, that can be targeted to LH-RH receptors on breast carcinomas. METHODS. Nude mice bearing MX-1 hormone-independent, doxorubicin-resistant human breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 and [D-Lys6]LH-RH. Tumor growth and changes in hematologic parameters were evaluated. Receptors for LH-RH were investigated by radioreceptor assays, and the expression of their mRNA was determined by reverse transcriptase-polymerase chain reaction. RESULTS. AN-207 caused complete regression of MX-1 tumors in all 10 animals, and they were still tumor free 60 days after treatment. In contrast, after therapy with AN-201 or the mixture of AN-201 and [D-Lys6]LH-RH, the regression of most MX-1 tumors was only transitory. AN-201 caused the death of 1 of the 10 animals and significantly greater leukopenia than AN-207, which produced no toxic deaths. Radioreceptor assays revealed high affinity binding sites for LH-RH on tumor cell membranes. The expression of mRNA for LH-RH receptors also was found in tumors. CONCLUSIONS. The results of this study indicate thai powerful, targeted cytotoxic LH-RH analogs such as AN-207 could be considered for the treatment of human breast carcinomas that possesses receptors for LH-RH.

AB - BACKGROUND. Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in about 50% of human breast carcinomas. A highly potent cytotoxic agent, 2-pyrrolinodoxorubicin (AN-201), was linked to the agonist [D- Lys6]LH-RH to form a cytotoxic LH-RH analog, AN-207, that can be targeted to LH-RH receptors on breast carcinomas. METHODS. Nude mice bearing MX-1 hormone-independent, doxorubicin-resistant human breast carcinomas were injected intravenously with vehicle (control), 250 nmol/kg doses of AN-201, AN-207, or an unconjugated mixture of AN-201 and [D-Lys6]LH-RH. Tumor growth and changes in hematologic parameters were evaluated. Receptors for LH-RH were investigated by radioreceptor assays, and the expression of their mRNA was determined by reverse transcriptase-polymerase chain reaction. RESULTS. AN-207 caused complete regression of MX-1 tumors in all 10 animals, and they were still tumor free 60 days after treatment. In contrast, after therapy with AN-201 or the mixture of AN-201 and [D-Lys6]LH-RH, the regression of most MX-1 tumors was only transitory. AN-201 caused the death of 1 of the 10 animals and significantly greater leukopenia than AN-207, which produced no toxic deaths. Radioreceptor assays revealed high affinity binding sites for LH-RH on tumor cell membranes. The expression of mRNA for LH-RH receptors also was found in tumors. CONCLUSIONS. The results of this study indicate thai powerful, targeted cytotoxic LH-RH analogs such as AN-207 could be considered for the treatment of human breast carcinomas that possesses receptors for LH-RH.

KW - Breast carcinoma

KW - Cytotoxic LH-RH analog

KW - MX-1 human breast carcinoma xenograft

KW - Receptor targeted chemotherapy

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