Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals

J. Pinski, Andrew V Schally, T. Yano, K. Szepeshazi, G. Halmos, K. Groot, A. M. Comaru- Schally, S. Radulovic, A. Nagy

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The effects of hybrid cytotoxic LH-RH analogs, produced by linking anthraquinone or methotrexate to carrier LH-RH agonist [D-Lys6]LH-RH, were evaluated in Copenhagen-Fisher F1 rats bearing Dunning R-3327H prostate adenocarcinoma. The two cytotoxic LH-RH analogs T-98 [(D-Lys6)LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone (G-HMAQ)], and AJ-04 [(D-Lys6)LH- RH linked to methotrexate (MTX)], carrier [D-Lys6]LH-RH, or the free cytotoxic compounds MTX and G-HMAQ were administered from Alzet Osmotic minipumps for 7-8 weeks. The cytotoxic LH-RH analogs caused somewhat greater tumor growth inhibition than the carrier peptide, while anthraquinone or methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary-gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in tumors treated with AJ-04, T-98, [D-Lys6]LH-RH, or by castration than in those of controls. Serum hormone levels were lowered by both carrier peptide and cytotoxic analogs, LH being substantially depressed, and testosterone not detectable. These results and other findings indicate that LH-RH analogs containing cytotoxic radicals anthraquinone or methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic LH-RH analogs to tumors such as prostate cancer, which have receptors for LH-RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted chemotherapy, might be of practical therapeutic importance for the management of advanced prostate cancers, which eventually relapse after palliative hormonal therapy.

Original languageEnglish
Pages (from-to)165-178
Number of pages14
JournalProstate
Volume23
Issue number2
StatePublished - Jan 1 1993
Externally publishedYes

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Gonadotropin-Releasing Hormone
Prostatic Neoplasms
Growth
Methotrexate
Anthraquinones
Prostate
Neoplasms
Peptides
Seminal Vesicles
Castration
Palliative Care
Mitosis
Androgens
Testosterone
Testis
Adenocarcinoma
Hormones
Apoptosis
Recurrence
Drug Therapy

ASJC Scopus subject areas

  • Urology

Cite this

Pinski, J., Schally, A. V., Yano, T., Szepeshazi, K., Halmos, G., Groot, K., ... Nagy, A. (1993). Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals. Prostate, 23(2), 165-178.

Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals. / Pinski, J.; Schally, Andrew V; Yano, T.; Szepeshazi, K.; Halmos, G.; Groot, K.; Comaru- Schally, A. M.; Radulovic, S.; Nagy, A.

In: Prostate, Vol. 23, No. 2, 01.01.1993, p. 165-178.

Research output: Contribution to journalArticle

Pinski, J, Schally, AV, Yano, T, Szepeshazi, K, Halmos, G, Groot, K, Comaru- Schally, AM, Radulovic, S & Nagy, A 1993, 'Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals', Prostate, vol. 23, no. 2, pp. 165-178.
Pinski J, Schally AV, Yano T, Szepeshazi K, Halmos G, Groot K et al. Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals. Prostate. 1993 Jan 1;23(2):165-178.
Pinski, J. ; Schally, Andrew V ; Yano, T. ; Szepeshazi, K. ; Halmos, G. ; Groot, K. ; Comaru- Schally, A. M. ; Radulovic, S. ; Nagy, A. / Inhibition of growth of experimental prostate cancer in rats by LH-RH analogs linked to cytotoxic radicals. In: Prostate. 1993 ; Vol. 23, No. 2. pp. 165-178.
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abstract = "The effects of hybrid cytotoxic LH-RH analogs, produced by linking anthraquinone or methotrexate to carrier LH-RH agonist [D-Lys6]LH-RH, were evaluated in Copenhagen-Fisher F1 rats bearing Dunning R-3327H prostate adenocarcinoma. The two cytotoxic LH-RH analogs T-98 [(D-Lys6)LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone (G-HMAQ)], and AJ-04 [(D-Lys6)LH- RH linked to methotrexate (MTX)], carrier [D-Lys6]LH-RH, or the free cytotoxic compounds MTX and G-HMAQ were administered from Alzet Osmotic minipumps for 7-8 weeks. The cytotoxic LH-RH analogs caused somewhat greater tumor growth inhibition than the carrier peptide, while anthraquinone or methotrexate alone, administered in equimolar doses, were ineffective. The inhibition of androgen sensitive organs (testes, ventral prostates, and seminal vesicles) was pronounced with both carrier and cytotoxic analogs, showing the latter to be fully hormonally active in suppressing the pituitary-gonadal axis. Histological changes were also evaluated. The inhibition of mitosis and the frequency of apoptosis were higher in tumors treated with AJ-04, T-98, [D-Lys6]LH-RH, or by castration than in those of controls. Serum hormone levels were lowered by both carrier peptide and cytotoxic analogs, LH being substantially depressed, and testosterone not detectable. These results and other findings indicate that LH-RH analogs containing cytotoxic radicals anthraquinone or methotrexate retain their hormonal activity after administration in vivo, and can effectively inhibit tumor growth. Extensive further studies are required on this new class of compounds, but apparent binding of cytotoxic LH-RH analogs to tumors such as prostate cancer, which have receptors for LH-RH, could greatly reduce peripheral toxicity of chemotherapeutic agents. This approach, based on targeted chemotherapy, might be of practical therapeutic importance for the management of advanced prostate cancers, which eventually relapse after palliative hormonal therapy.",
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