Receptors for somatostatin (SST) found on brain tumors could be used for targeting of chemotherapeutic agents. This study was conducted to investigate the effects of targeted cytotoxic SST analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201), a potent derivative of doxorubicin (DOX) linked to somatostatin analogue RC-121, on the growth of SST receptor-positive U-87 MG human glioblastomas. Nude mice bearing U-87 MG xenografts received i.v. saline or equimolar doses of AN-238 or AN-201 (150 nmol/kg). Experiments also included groups that were administered RC-121 prior to the injection of AN-238, and groups injected with AN-162, a cytotoxic SST analogue similar to AN-238 but containing DOX instead of AN-201. Tumor volume, weight, and burden were determined. The effect of AN-238 and AN-201 on the survival time of nude mice bearing orthotopically implanted U-87 MG tumors was also evaluated. The binding of AN-238 to U-87 MG tumors was determined by radioreceptor assay and SST receptor (SSTR) subtype by reverse transcription-PCR. Nineteen days after a single administration of AN-238 the growth of U-87 MG tumors in nude mice was significantly inhibited (P = 0.00168), whereas two injections of AN-238 produced the regression of tumors (P = 0.0046). AN-201 was toxic and ineffective at the same dose. The antitumor effect on AN-238 could be blocked by pretreatment of the tumor-bearing mice with RC-121. The mean survival time of nude mice inoculated orthotopically with U-87 MG cells into the brain was significantly prolonged by treatment with AN-238 (P = 0.0099). AN-162 failed to inhibit significantly the growth of U-87 MG xenografts. High affinity binding sites for SST and mRNA for SST-2 receptor subtype were detected in U-87 MG tumors. Cytotoxic SST analogue AN-238 can be targeted to SST receptors on U-87 MG human glioblastomas to produce powerful inhibition of growth.