Inhibition of PC-3 human androgen-independent prostate cancer and its metastases by cytotoxic somatostatin analogue AN-238

• Published in: Cancer research (Chicago, Ill.) Ill.), 1999-04, Vol.59 (8), p.1947-1953
• Main Authors: PLONOWSKI, A, SCHALLY, A. V, NAGY, A, BAODONG SUN, SZEPESHAZI, K
• Format: Article
• Language: English
• Subjects: Androgens - metabolism; Animals; Antibiotics, Antineoplastic - therapeutic use; Antineoplastic agents; Biological and medical sciences; Chemotherapy; Doxorubicin - analogs & derivatives; Doxorubicin - therapeutic use; Gene Expression - drug effects; Humans; Lymphatic Metastasis - prevention & control; Male; Medical sciences; Mice; Mice, Nude; Neoplasm Metastasis - prevention & control; Neoplasm Transplantation; Pharmacology. Drug treatments; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; Pyrroles - therapeutic use; Receptors, Somatostatin - biosynthesis; Somatostatin - analogs & derivatives; Transplantation, Heterologous; Tumor Cells, Cultured
• ISSN: 0008-5472; 1538-7445

We evaluated whether AN-238, the cytotoxic analogue of somatostatin (SST) consisting of the radical 2-pyrrolinodoxorubicin (AN-201) linked covalently to the SST octapeptide carrier RC-121 (D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2), could be used for targeting human primary and metastatic prostate carcinomas that express SST receptors (SSTRs). The antitumor activity and toxicity of AN-238 and its components were first characterized in nude mice bearing s.c. xenografts of PC-3 human androgen-independent prostate cancer. In experiment 1, AN-238 was injected once i.v. at 200 nmol/kg when the mean volume of s.c. tumors was about 30 mm3. Administration of AN-238 inhibited tumor growth, as shown by a 74% decrease in tumor volume and by a 71% reduction in tumor weight after 7 weeks as compared with the control group. AN-201 at an equimolar dose did not show any antitumor activity. The mortality was 14.3% (one of seven mice) in the AN-238-treated group and 47% (three of seven mice) in mice that received AN-201. In experiment 2, two i.v. injections of AN-238 at 150 nmol/kg were given 10 days apart when the tumors measured 65-70 mm3. A significant inhibition of tumor volume (62.3%; P < 0.001) and tumor weight (61.1%; P < 0.01) was observed after 4 weeks of treatment. AN-201, given alone at the same dose or coadministered with RC-121, had no significant effect on PC-3 tumors. The suppression of tumor growth induced by AN-238 was accompanied by a significant enhancement of apoptosis (P < 0.01). There were similar side effects in all treated groups, which included a transient loss of body weight and leukopenia. The effectiveness of AN-238 in a metastatic model was then investigated in animals implanted orthotopically with 2 x 10(6) PC-3 cells. Two i.v. injections of AN-238 or AN-201 at 150 nmol/kg were administered 10 days apart at 10 weeks after intraprostatic inoculation of PC-3 cells. After 4 weeks of treatment, the mean weight of primary tumors in animals receiving AN-238 was 77% lower (P < 0.01) than that in controls. This reduction was also significantly greater (P < 0.05) than that in animals given AN-201, which showed only a 34% inhibition (nonsignificant versus controls). All control animals and four of six (67%) mice treated with AN-201 developed metastases in the lymph nodes; however, no lymphatic spread of cancer was found in the AN-238-treated group. Using reverse transcription-PCR analysis, we demonstrated the expression of SSTR2 and SSTR5 in intraprostatic