Combination treatment of nitrosamiee-induced pancreatic cancers in hamsters with analogs of LH-RH and a bombesin/GRP antagonist

Karoly Szepeshazi, Gabor Halmos, Kate Groot, Andrew V Schally

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Analogs of luteinizing hormone-releasing hormone (LH-RH) and bombesin/gastrin-releasing peptide were previously shown to inhibit the growth of experimental pancreatic cancers. In the present study, in an attempt to increase the efficacy of therapy, female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amineinduced pancreatic cancers were treated for 2 mo with a combination of LH-RH agonist [D-Trp6]LH-RH or antagonist [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6-Ala10]LH-RH (SB-75) and bombesin/GRP antagonistD-Tpi6, Leu13**(CH2NH)Leu14bombesin(6-14) (RC-3095). The results were compared to those obtained by treatment with same doses of single peptides. LH-RH analogs and bombesin antagonist given alone significantly reduced the number of tumorous animals and decreased weight of pancreata by 46-71% and weight of tumorous pancreas by 38-64%. Histology showed lower mitotic activity and a decreased number of AgNORs in tumor cells from treated animals. Enhanced apoptosis was also observed after treatment with the LH-RH analogs. Combination therapy had no superior inhibitory effect on tumors compared to single peptides, by practically all the parameters analyzed. The reasons for this lack of potentiation are not clear. The tumor inhibitory effect of bombesin antagonists appears to be mediated by interference with EGF-receptor mechanisms. In the present study, although a significant downregulation of EGF-receptors was found in tumors treated with combination, the decrease in binding capacity for EGF was maximal in the group treated with RC-3095 alone. Since intracellular signaling mechanisms are common for LH-RH and bombesin-like peptides, it is possible that second messengers were already maximally utilized by treatment with single peptides. Bombesin/GRP abolished the apoptosis enhancing effect of the LH-RH analogs, probably by interference in intracellular mechanisms. A more complete elucidation of the exact mechanisms of action of LH-RH and bombesin/GRP analogs is necessary for planning a successful combination therapy with these peptides.

Original languageEnglish
Pages (from-to)141-149
Number of pages9
JournalInternational Journal of Pancreatology
Volume16
Issue number2-3
DOIs
StatePublished - Oct 1 1994
Externally publishedYes

Fingerprint

Bombesin
Pancreatic Neoplasms
Gonadotropin-Releasing Hormone
Cricetinae
Peptides
Therapeutics
Pancreas
Neoplasms
Gastrin-Releasing Peptide
Apoptosis
Hormone Antagonists
Weights and Measures
Mesocricetus
Second Messenger Systems
Epidermal Growth Factor Receptor
Epidermal Growth Factor
Histology
Down-Regulation

Keywords

  • AgNORs
  • apoptosis
  • bombesin/GRP antagonist
  • LH-RH analogs
  • pancreatic cancer
  • receptors

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology
  • Endocrinology

Cite this

Combination treatment of nitrosamiee-induced pancreatic cancers in hamsters with analogs of LH-RH and a bombesin/GRP antagonist. / Szepeshazi, Karoly; Halmos, Gabor; Groot, Kate; Schally, Andrew V.

In: International Journal of Pancreatology, Vol. 16, No. 2-3, 01.10.1994, p. 141-149.

Research output: Contribution to journalArticle

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abstract = "Analogs of luteinizing hormone-releasing hormone (LH-RH) and bombesin/gastrin-releasing peptide were previously shown to inhibit the growth of experimental pancreatic cancers. In the present study, in an attempt to increase the efficacy of therapy, female Syrian golden hamsters with N-nitrosobis(2-oxopropyl)amineinduced pancreatic cancers were treated for 2 mo with a combination of LH-RH agonist [D-Trp6]LH-RH or antagonist [Ac-D-Nal(2)1,D-Phe(4Cl)2,D-Pal(3)3,D-Cit6-Ala10]LH-RH (SB-75) and bombesin/GRP antagonistD-Tpi6, Leu13**(CH2NH)Leu14bombesin(6-14) (RC-3095). The results were compared to those obtained by treatment with same doses of single peptides. LH-RH analogs and bombesin antagonist given alone significantly reduced the number of tumorous animals and decreased weight of pancreata by 46-71{\%} and weight of tumorous pancreas by 38-64{\%}. Histology showed lower mitotic activity and a decreased number of AgNORs in tumor cells from treated animals. Enhanced apoptosis was also observed after treatment with the LH-RH analogs. Combination therapy had no superior inhibitory effect on tumors compared to single peptides, by practically all the parameters analyzed. The reasons for this lack of potentiation are not clear. The tumor inhibitory effect of bombesin antagonists appears to be mediated by interference with EGF-receptor mechanisms. In the present study, although a significant downregulation of EGF-receptors was found in tumors treated with combination, the decrease in binding capacity for EGF was maximal in the group treated with RC-3095 alone. Since intracellular signaling mechanisms are common for LH-RH and bombesin-like peptides, it is possible that second messengers were already maximally utilized by treatment with single peptides. Bombesin/GRP abolished the apoptosis enhancing effect of the LH-RH analogs, probably by interference in intracellular mechanisms. A more complete elucidation of the exact mechanisms of action of LH-RH and bombesin/GRP analogs is necessary for planning a successful combination therapy with these peptides.",
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