Regression of rat Dunning R-3327-H prostate carcinoma by treatment with targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 containing 2-pyrrolinodoxorubicin

Andreas Jungwirth, Andrew V Schally, Attila Nagy, Jacek Pinski, Kate Groot, Georg Galvan, Karoly Szepeshazi, Gabor Halmos

Research output: Contribution to journalArticle

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Abstract

The effects of AN-207, a new targeted cytotoxic analog of LH-RH, were evalued in rats bearing hormone-dependent Dunning R-3327-H prostate carcinomas. AN-207 consists of the agonist [D-Lys6]LH-RH linked to 2-pyrrolinodoxorubicin, an intensely potent derivative of doxorubicin. In the first experiment, 2-pyrrolinodoxorubicin was administered at a concentration of 50 nmol/kg, as a single drug (AN-201) and as an unconjugated mixture with [D-Lys6]LH-RH or conjugated to the carrier [D-Lys6]LH-RH (AN-207). Following the second administration of radical AN-201 alone or mixed with the carrier, all rats died with signs of general toxicity, but all animals treated with the conjugate AN-207, survived. After 5 weeks of treatment with a total dose of 150 nmol/kg AN-207, the tumors regressed from an initial volume of 8.35 ± 1.7 cm3 to 4.47 ± 0.8 cm3, while tumors in the control group measured 17.84 ± 2.2 cm3. The therapy with AN-207 also significantly reduced tumor weight and tumor burden. In the second experiment, we compared the efficacy and toxicity of 3 injections of 25 nmol/kg AN-201 or 25 nmol/kg and 50 nmol/kg AN-207. The initial tumor volume in all groups was between 3.9 and 4.5 cm3. After 5 weeks of therapy, the tumors of rats treated with 50 nmol/kg AN-207 regressed to 2.3 ± 0.51 cm3, whereas 25 nmol/kg AN-201 was still toxic in contrast to 25 nmol/kg AN-207, while the reduction in final tumor volume was similar (6.76 ± 1.4 cm3 and 6.74 ± 1 cm3, respectively), as compared to 15.6 ± 2.2 cm3 for untreated animals. High capacity LH-RH receptors were found in the membranes of untreated Dunning tumor specimens, but after treatment with AN-207, they could no longer be detected. This is the first demonstration that the new targeted cytotoxic LH-RH analog AN-207 is an effective antitumor agent. Our work indicates that the cytotoxic analog AN-207 is much less toxic than the antineoplastic radical (AN-201) incorporated, and significantly more active in inhibiting tumor growth. Further development of approaches based on targeted cytotoxic analog AN-207 may lead to major improvements in current palliative therapy of prostate cancer.

Original languageEnglish
Pages (from-to)877-884
Number of pages8
JournalInternational Journal of Oncology
Volume10
Issue number5
StatePublished - May 29 1997
Externally publishedYes

Fingerprint

Gonadotropin-Releasing Hormone
Prostate
Carcinoma
Tumor Burden
Therapeutics
Poisons
Neoplasms
Antineoplastic Agents
AN 207
AN 204
LH Receptors
Palliative Care
Doxorubicin
Prostatic Neoplasms
Hormones

Keywords

  • 2-pyrrolinodoxorubicin
  • Dunning tumor
  • LH-RH
  • prostate carcinoma
  • targeted chemotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Regression of rat Dunning R-3327-H prostate carcinoma by treatment with targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 containing 2-pyrrolinodoxorubicin. / Jungwirth, Andreas; Schally, Andrew V; Nagy, Attila; Pinski, Jacek; Groot, Kate; Galvan, Georg; Szepeshazi, Karoly; Halmos, Gabor.

In: International Journal of Oncology, Vol. 10, No. 5, 29.05.1997, p. 877-884.

Research output: Contribution to journalArticle

Jungwirth, Andreas ; Schally, Andrew V ; Nagy, Attila ; Pinski, Jacek ; Groot, Kate ; Galvan, Georg ; Szepeshazi, Karoly ; Halmos, Gabor. / Regression of rat Dunning R-3327-H prostate carcinoma by treatment with targeted cytotoxic analog of luteinizing hormone-releasing hormone AN-207 containing 2-pyrrolinodoxorubicin. In: International Journal of Oncology. 1997 ; Vol. 10, No. 5. pp. 877-884.
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abstract = "The effects of AN-207, a new targeted cytotoxic analog of LH-RH, were evalued in rats bearing hormone-dependent Dunning R-3327-H prostate carcinomas. AN-207 consists of the agonist [D-Lys6]LH-RH linked to 2-pyrrolinodoxorubicin, an intensely potent derivative of doxorubicin. In the first experiment, 2-pyrrolinodoxorubicin was administered at a concentration of 50 nmol/kg, as a single drug (AN-201) and as an unconjugated mixture with [D-Lys6]LH-RH or conjugated to the carrier [D-Lys6]LH-RH (AN-207). Following the second administration of radical AN-201 alone or mixed with the carrier, all rats died with signs of general toxicity, but all animals treated with the conjugate AN-207, survived. After 5 weeks of treatment with a total dose of 150 nmol/kg AN-207, the tumors regressed from an initial volume of 8.35 ± 1.7 cm3 to 4.47 ± 0.8 cm3, while tumors in the control group measured 17.84 ± 2.2 cm3. The therapy with AN-207 also significantly reduced tumor weight and tumor burden. In the second experiment, we compared the efficacy and toxicity of 3 injections of 25 nmol/kg AN-201 or 25 nmol/kg and 50 nmol/kg AN-207. The initial tumor volume in all groups was between 3.9 and 4.5 cm3. After 5 weeks of therapy, the tumors of rats treated with 50 nmol/kg AN-207 regressed to 2.3 ± 0.51 cm3, whereas 25 nmol/kg AN-201 was still toxic in contrast to 25 nmol/kg AN-207, while the reduction in final tumor volume was similar (6.76 ± 1.4 cm3 and 6.74 ± 1 cm3, respectively), as compared to 15.6 ± 2.2 cm3 for untreated animals. High capacity LH-RH receptors were found in the membranes of untreated Dunning tumor specimens, but after treatment with AN-207, they could no longer be detected. This is the first demonstration that the new targeted cytotoxic LH-RH analog AN-207 is an effective antitumor agent. Our work indicates that the cytotoxic analog AN-207 is much less toxic than the antineoplastic radical (AN-201) incorporated, and significantly more active in inhibiting tumor growth. Further development of approaches based on targeted cytotoxic analog AN-207 may lead to major improvements in current palliative therapy of prostate cancer.",
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