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Antitumoral Activity of Bombesin Analogues on Small Cell Lung Cancer Xenografts: Relationship with Bombesin Receptor Expression

Ipsen Biotech, 30 rue Cambronne, 75737 Paris Cedex 15 [F. T.]; Laboratoire de Biologie des Metastases, Institut pour la Recherche sur le Cancer—Centre National de la Recherche Scientifique, 7 rue Guy Moquet, 94801 Villejuif [E. A., M. J., M. F. P.], France; and Universidad Central de Venezuela, Facultad de Ciencias, Escuela Biologia, Caracas, Venezuela [F. A.]

Gastrin releasing peptide (GRP), the human homologue of bombesin (BN), is an autocrine growth factor for small cell lung cancer (SCLC) cells. The synthetic octapeptides [D-cpa¹-ß-Leu⁸-des-Met⁹]litorin (BIM 26182) and [D-Phe⁶-Leu¹³-CH₂NH-Cpa¹⁴]bombesin(6–14)NH₂ (BIM 26189) are potent GRP/BN antagonists of the proliferation of 3T3 and rat pancreas cells. The effect of these analogues on the proliferation of four SCLC cell lines (SCLC 6, SCLC 41, SCLC 75, SCLC 74R) was tested in vitro and in vivo. Two of these SCLC lines (SCLC 41M and SCLC 75) had receptors for BN/GRP and expressed the prepro-GRP mRNA. BIM 26182 and BIM 26189 inhibited [³H]thymidine incorporation into the DNA of SCLC 41 cells, stimulated [³H]thymidine incorporation in SCLC 6, and had no effect on the two other cell lines. The SCLC implanted s.c. in nude mice were treated with either BIM 26182 or BIM 26189. BIM 26182 and BIM 26189 injected at the doses of 50 µg twice a day (s.c.) around the tumor for 10 to 21 days delayed the growth of SCLC 41 and of SCLC 75. The maximal effect was observed during the treatment period, after which the tumors regrew, suggesting a cytostatic effect of these peptides. No inhibitory effect of the peptides on SCLC 74R or SCLC 6 growth was observed. These data suggest that GRP antagonists are able to inhibit the in vitro and in vivo growth of BN/GRP receptors-positive SCLC.

¹ To whom requests for reprints should be addressed, at Ipsen Biotech, 30 rue Cambronne, 75015 Paris, France.

Received 6/11/91. Accepted 7/ 9/92.

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