Targeted cytotoxic analogue of bombesin/gastrin-releasing peptide inhibits the growth of H-69 human small-cell lung carcinoma in nude mice

H. Kiaris, Andrew V Schally, A. Nagy, B. Sun, P. Armatis, K. Szepeshazi

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Recently we developed a powerful cytotoxic analogue of bombesin AN-215, in which the bombesin-like carrier peptide Gln-Trp-Ala-Val-Gly-His-Leu-Ψ(CH2-NH)-Leu-NH2(RC-3094) is conjugated to a potent derivative of doxorubicin, 2-pyrrolinodoxorubicin (AN-201). Small-cell lung carcinomas (SCLCs) are known to express high levels of bombesin receptors. We evaluated whether these receptors could be used for targeting cytotoxic bombesin analogue to H-69 SCLC cells. H-69 cells were xenografted into male nude mice, which then received an intravenous injection of AN-215, cytotoxic radical AN-201, the carrier peptide RC-3094 alone or unconjugated mixture of RC-3094 and AN-201. The levels of mRNA for bombesin receptor subtypes were evaluated by reverse transcription-polymerase chain reaction. In vitro, both the analogue AN-215 and the radical AN-201 showed strong antiproliferative effects on H-69 cells, AN-215 requiring more time to exert its action at 10-8 M concentration than AN-201. In vivo, the growth of H-69 SCLC tumours was significantly inhibited by the treatment with 200 nmol kg-1 of AN-215, while equimolar doses of the cytotoxic radical AN-201 or the mixture of AN-201 and the carrier peptide were toxic and produced only a minor tumour inhibition as compared with control groups. mRNA for bombesin receptor subtypes 2 (BRS-2) and 3 (BRS-3) was detected in H-69 tumours. The mRNA levels for BRS-3, but not for BRS-2, were lower in the AN-215-treated tumours as compared with controls. Our results demonstrate that the cytotoxic bombesin analogue AN-215 could be considered for targeted therapy of tumours, such as SCLC, that express bombesin receptors.

Original languageEnglish
Pages (from-to)966-971
Number of pages6
JournalBritish Journal of Cancer
Volume81
Issue number6
DOIs
StatePublished - Nov 17 1999
Externally publishedYes

Fingerprint

Gastrin-Releasing Peptide
Bombesin
Small Cell Lung Carcinoma
Nude Mice
Bombesin Receptors
Growth
Neoplasms
Messenger RNA
Peptides
AN 204
Poisons
AN 215
Intravenous Injections
Doxorubicin
Reverse Transcription
Polymerase Chain Reaction
Control Groups

Keywords

  • Bombesin receptor
  • Cancer therapy
  • Doxorubicin
  • hGRPR
  • hNMSR
  • Hormone analogues
  • RT-PCR
  • Tumour inhibition
  • Tumour targeting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeted cytotoxic analogue of bombesin/gastrin-releasing peptide inhibits the growth of H-69 human small-cell lung carcinoma in nude mice. / Kiaris, H.; Schally, Andrew V; Nagy, A.; Sun, B.; Armatis, P.; Szepeshazi, K.

In: British Journal of Cancer, Vol. 81, No. 6, 17.11.1999, p. 966-971.

Research output: Contribution to journalArticle

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AU - Armatis, P.

AU - Szepeshazi, K.

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