title: Effective treatment of H838 human non-small cell lung carcinoma with a targeted cytotoxic somatostatin analog, AN-238.
abstract: The accumulation of radioactive somatostatin analog [111In]pentetreotide in non-small cell lung cancer (non-SCLC) during scintigraphy of patients provides a rationale for investigating the efficacy of somatostatin receptor-based chemotherapy in non-SCLC. Consequently, in this study, we evaluated the antitumor effects of cytotoxic somatostatin analog AN-238 on H838 human non-SCLC xenografted into nude mice in comparison with its cytotoxic radical, 2-pyrrolinodoxorubicin (AN-201). The expression of messenger RNA (mRNA) for human somatostatin receptor subtypes 2 (hsst2) and 5 (hsst5) in H838 cells, and tumors was also investigated using reverse-transcription polymerase chain reaction (RT-PCR). Somatostatin receptors on H838 tumors were characterized by ligand competition assay using radiolabeled somatostatin analog, RC-160. Three i.v. injections of AN-238 at 150 nmol/kg, given on days 1, 7 and 21, resulted in a significant (p<0.05) tumor growth inhibition, the final tumor volume being 60% smaller than in the controls. The tumor doubling time was also extended significantly (p<0.05) from 9.65+/-0.56 days in the controls to 17.52+/-3.3 days. Only one of 8 mice died due to toxicity. In contrast, cytotoxic radical AN-201 was ineffective and more toxic, killing 2 of 7 animals. mRNA for hsst2 was found in H838 xenografts, but not in H838 cells from which the xenografts originated. Interestingly, H838 cells grown in a special, serum-free medium did express mRNA for hsst2. mRNA for hsst5 was not found in any samples tested. Binding studies demonstrated the presence of high affinity (K(d) = 7.3+/-1.2 nM) binding sites for RC-160 with a mean maximal binding capacity (B(max)) of 953.3+/-45.3 fmol/mg protein. AN-238 at 3.14+/-0.93 nM concentration displaced 50% of radiolabeled RC-160 binding to somatostatin receptors in H838 tumors. Our results indicate that patients with inoperable non-SCLC may benefit from chemotherapy targeted to somatostatin receptors based on AN-238.
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70112-1262, USA.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szereday
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Schally
authors.forename: Karoly
authors.initials: K
authors.lastname: Szepeshazi
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Bajo
authors.forename: Francine
authors.initials: F
authors.lastname: Hebert
authors.forename: Gabor
authors.initials: G
authors.lastname: Halmos
authors.forename: Attila
authors.initials: A
authors.lastname: Nagy
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003603:Cytotoxins / Q000627:therapeutic use; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D007958:Leukocyte Count; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011758:Pyrroles / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C110845:AN 238; D003603:Cytotoxins; D011758:Pyrroles; C098751:AN 204; D004317:Doxorubicin