TY - JOUR
T1 - A targeted cytotoxic somatostatin (SST) analogue, AN-238, inhibits the growth of H-69 small-cell lung carcinoma (SCLC) and H-157 non-SCLC in nude mice
AU - Kiaris, H.
AU - Schally, A. V.
AU - Nagy, A.
AU - Szepeshazi, K.
AU - Hebert, F.
AU - Halmos, G.
N1 - Funding Information:
We thank P. Armatis for help with tissue cultures, Dr B. Csernus for help with SSTR analyses, A. Feil for histochemical work and H. Valerio for technical assistance. The work described in this paper was supported by the Medical Research Service of the Veterans Affairs Department and a grant from ASTA Medica (Frankfurt am Main, Germany) to Tulane University (all to A.V.S.).
Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 2001
Y1 - 2001
N2 - Recently, we developed a cytotoxic analogue of somatostatin (SST), AN-238, in which the SST carrier peptide RC-121 was linked to 2-pyrrolinodoxorubicin (2-pyrrolino-DOX) (AN-201), a potent derivative of doxorubicin. AN-238 can be targeted to SST receptors (SSTRs) on tumours. In the present study, we evaluated the effects of AN-238 on the growth of H-69 small-cell lung carcinoma (SCLC) and H-157 non-SCLC xenografted into nude mice. High affinity binding sites for SST are present in H-69 SCLC and were now detected in H-157 non-SCLC xenografts, but not in H-157 cells. A strong expression of the human SSTR subtype 2 (hSSTR-2) and a weaker expression of subtype 5 (hSSTR-5) was found in H-69 SCLC cells, but not in H-157 non-SCLC cells. However, a strong expression of mRNA for mouse (m)SSTR-2 could be detected in H-157 xenografts. AN-238 effectively inhibited the growth of H-69 SCLC tumours in nude mice. Twenty-six days after a single injection of AN-238 at 200 nmol/kg, the volume of H-69 tumours was decreased by approximately 55% (P < 0.05) compared with the controls, while AN-201 at the same dose was highly toxic and produced only a minor tumour inhibition. To evaluate the potency of multiple doses of AN-238, nude mice bearing H-69 SCLC received three injections of AN-238 at 150 nmol/kg on days 1, 12 and 28. In the period of 42 days after the first injection, the growth rate of H-69 tumours was approximately 50% lower than that of controls. In nude mice bearing H-157 non-SCLC tumours, a single i.v. administration of AN-238 at 200 nmol/kg inhibited tumour volume by 91% after 28 days (P < 0.01 compared with controls). AN-201 was toxic and ineffective at the same dose. Two injections of AN-238 at 150 nmol/kg given on days 1 and 18 produced 83% inhibition of H-157 tumour growth (P < 0.01 versus controls). AN-238 given as a single dose of 200 nmol/kg induced necrosis, while two injections of 150 nmol/kg induced apoptosis in the tumour tissue. Our results indicate that targeted cytotoxic SST analogue AN-238 could be considered for therapy of both SCLC and non-SCLC.
AB - Recently, we developed a cytotoxic analogue of somatostatin (SST), AN-238, in which the SST carrier peptide RC-121 was linked to 2-pyrrolinodoxorubicin (2-pyrrolino-DOX) (AN-201), a potent derivative of doxorubicin. AN-238 can be targeted to SST receptors (SSTRs) on tumours. In the present study, we evaluated the effects of AN-238 on the growth of H-69 small-cell lung carcinoma (SCLC) and H-157 non-SCLC xenografted into nude mice. High affinity binding sites for SST are present in H-69 SCLC and were now detected in H-157 non-SCLC xenografts, but not in H-157 cells. A strong expression of the human SSTR subtype 2 (hSSTR-2) and a weaker expression of subtype 5 (hSSTR-5) was found in H-69 SCLC cells, but not in H-157 non-SCLC cells. However, a strong expression of mRNA for mouse (m)SSTR-2 could be detected in H-157 xenografts. AN-238 effectively inhibited the growth of H-69 SCLC tumours in nude mice. Twenty-six days after a single injection of AN-238 at 200 nmol/kg, the volume of H-69 tumours was decreased by approximately 55% (P < 0.05) compared with the controls, while AN-201 at the same dose was highly toxic and produced only a minor tumour inhibition. To evaluate the potency of multiple doses of AN-238, nude mice bearing H-69 SCLC received three injections of AN-238 at 150 nmol/kg on days 1, 12 and 28. In the period of 42 days after the first injection, the growth rate of H-69 tumours was approximately 50% lower than that of controls. In nude mice bearing H-157 non-SCLC tumours, a single i.v. administration of AN-238 at 200 nmol/kg inhibited tumour volume by 91% after 28 days (P < 0.01 compared with controls). AN-201 was toxic and ineffective at the same dose. Two injections of AN-238 at 150 nmol/kg given on days 1 and 18 produced 83% inhibition of H-157 tumour growth (P < 0.01 versus controls). AN-238 given as a single dose of 200 nmol/kg induced necrosis, while two injections of 150 nmol/kg induced apoptosis in the tumour tissue. Our results indicate that targeted cytotoxic SST analogue AN-238 could be considered for therapy of both SCLC and non-SCLC.
KW - Chemotherapy
KW - Doxorubicin
KW - Lung cancer
KW - Receptor
KW - Targeted analogue
KW - Tumour inhibition
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U2 - 10.1016/S0959-8049(00)00437-8
DO - 10.1016/S0959-8049(00)00437-8
M3 - Article
C2 - 11290438
AN - SCOPUS:0035094324
VL - 37
SP - 620
EP - 628
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 5
ER -