Effective treatment of experimental androgen sensitive and androgen independent intraosseous prostate cancer with targeted cytotoxic somatostatin analogue AN-238.

Abstract

PURPOSE:

The targeted cytotoxic somatostatin analogue AN-238, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to carrier octapeptide RC-121, is scheduled for clinical trials. To extend previous findings we tested AN-238 on human androgen sensitive MDA-PCa-2b prostate cancers grown subcutaneously and androgen independent LNCaP derived C4-2 prostate cancers xenografted into the tibiae of nude mice.

MATERIALS AND METHODS:

Changes in serum prostate specific antigen (PSA) levels were monitored by radioimmunoassay. Somatostatin receptors in tumor samples were characterized.

RESULTS:

Three intravenous injections of AN-238 at 150 nmol/kg doses inhibited the growth of subcutaneous MDA-PCa-2b tumors by 62% vs controls (p <0.05) and were more effective than equimolar doses of the radical AN-201 (p <0.05). AN-238 also decreased serum PSA levels by 62% vs controls (p <0.01). In nude mice bearing intra-osseous implanted C4-2 prostate cancers AN-238 decreased serum PSA levels by 65% compared with controls after 5 weeks of therapy (p <0.05), while AN-201 was ineffective. All AN-238 treated mice were alive at the termination of the experiment, while only 50% of controls and 60% of animals treated with AN-201 survived (p <0.01). Histological evaluation of intraosseous C4-2 tumors showed that AN-238 induced a significant increase in apoptosis (p <0.05). MDA-PCa-2b and C4-2 tumors showed high affinity binding for somatostatin and the expression of mRNA for somatostatin receptor subtypes 1, 2A and 5.

CONCLUSIONS:

The current study demonstrates the efficacy of the somatostatin analogue AN-238 for subcutaneous MDA-PCa-2b as well as for intraosseous C4-2 prostate cancers xenografted into nude mice. This targeted cytotoxic analogue could represent a new therapy for patients with advanced metastatic prostate carcinoma.

• Authors: Markus Letsch, Andrew V Schally, Karoly Szepeshazi, Gabor Halmos, Attilla Nagy
• Journal: The Journal of urology (J Urol) Vol. 171 Issue 2 Pt 1 Pg. 911-5 (Feb 2004) ISSN: 0022-5347 [Print] United States
• PMID: 14713852 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• AN 238
• Androgens
• Cytotoxins
• Drug Carriers
• Pyrroles
• Somatostatin
• Doxorubicin
• RC 121
• Octreotide

Topics

• Androgens (physiology)
• Animals
• Bone Neoplasms (drug therapy, secondary)
• Cell Line, Tumor
• Cytotoxins (administration & dosage, therapeutic use)
• Doxorubicin (administration & dosage, analogs & derivatives, therapeutic use)
• Drug Carriers
• Humans
• Male
• Mice
• Mice, Nude
• Octreotide (analogs & derivatives)
• Prostatic Neoplasms (drug therapy, pathology)
• Pyrroles (administration & dosage, therapeutic use)
• Somatostatin (analogs & derivatives)