The effectiveness of
chemotherapy targeted to
somatostatin (SST) receptors based on cytotoxic SST analogue
AN-238, consisting of
2-pyrrolinodoxorubicin (AN-201) linked to SST carrier octapeptide, was investigated in human
renal cell carcinomas (RCCs). SST receptors, which showed high-affinity binding for
AN-238, were found in the SW-839 RCC line with sst2A subtype and in the 786-0 RCC line, which expressed the sst5 subtype. CAKI-1 RCC, which does not express sst2A or sst5, was used as a negative control for testing the specificity of SST receptor targeting. Using microsatellite analysis,
AN-238 was shown to selectively inhibit the proliferation of 786-0 line, but not the CAKI-1 RCC line in vitro. The effects of three i.v.
injections of 150 nmol/kg of
AN-238 or
AN-201, given on days 1, 8, and 21, were evaluated in groups of nude mice bearing s.c. xenografts of SW-839 and 786-0 RCC. After 5 weeks, the volumes of SW-839 and 786-0 RCC
tumors were decreased by 67.2 (P < 0.05) and 78.3% (P < 0.01), respectively, whereas
AN-201 had no significant effect on
tumor growth. The inhibition of SST receptor-negative CAKI-1
tumors by
AN-238 was only marginal. To investigate the efficacy of SST receptor-targeted
chemotherapy in metastatic RCC, three i.v.
injections of
AN-238 or
AN-201 at 150 nmol/kg were given at biweekly intervals to nude mice implanted with 786-0
tumors under the renal
capsule. After 6 weeks, the weight of orthotopic
tumors treated with
AN-238 (55.3 +/- 44.3 mg) was significantly lower (87% reduction; P < 0.001) than that in the control group (414.2 +/- 41.0 mg) or in animals given
AN-201 (270.2 +/- 603 mg; P < 0.05). Five of six animals (83%), both in the control and the
AN-201 group, developed
metastases to lymph nodes, but only one of seven mice (14%) given
AN-238 showed lymphatic spread. Lung
metastases were found in 83% of controls and 50% of
AN-201 treated animals, but none occurred in mice treated with
AN-238. This study demonstrates that targeted cytotoxic SST analogue
AN-238 provides an effective
therapy for chemoresistant
neoplasms such as RCC. Because most clinical RCCs express SST receptors, this treatment modality might be beneficial to patients with metastatic disease.