In vitro and in vivo activity of alkylating bombesin receptor antagonists on small cell lung carcinoma.
Bombesin (BN) and bombesin-like peptides are autocrine growth factors for small cell lung carcinoma (SCLC). BN receptor antagonists can therefore find clinical application in the treatment of this highly malignant disease. Six peptides belonging to a new class of alkylating BN analogues have been selected according to their characteristics evidenced on Swiss 3T3 fibroblasts: high binding affinity to BN receptor, relevant inhibition (> 60%) of the proliferative stimulus induced by BN, long-lasting effect and specificity for BN receptor. The six peptides were able to bind BN receptors on SCLC cells and to inhibit the growth of two SCLC cell lines: NCI-H69 and NCI-N592. Conversely, they did not inhibit the growth of tumor cell lines devoid of BN receptors. Two of them were tested in vivo on N592 cells transplanted into nude mice. The peptide carrying a Cab [p-bis(2 chloroethyl)aminobenzoyl] moiety proved to be completely inactive. The second peptide, with a Melphalan moiety (Mel), showed a moderate activity (33-45% of tumor growth inhibition) without any toxicity. The low solubility of this compound prevented the use of the higher doses in vivo.
R & D Experimental Oncology Laboratory, Research Institute, Nerviano (MI), Italy.
M
M
Ciomei
W
W
Pastori
A
A
Pastori
R
R
de Castiglione
L
L
Gozzini
F
F
Corradi
D016475:3T3 Cells; D000477:Alkylating Agents / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001839:Bombesin / Q000031:analogs & derivatives; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000648:ultrastructure; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000648:ultrastructure; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; D001839:Bombesin; D008558:Melphalan