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


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.
Letsch
Markus
M
Endocrine, Polypeptide and Cancer Institute, Veterans Affairs Medical Center and Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Schally
Andrew V
AV
Szepeshazi
Karoly
K
Halmos
Gabor
G
Nagy
Attilla
A
D000728:Androgens / Q000502:physiology; D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use*; D004337:Drug Carriers; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D015282:Octreotide / Q000031:analogs & derivatives*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D013004:Somatostatin / Q000031:analogs & derivatives
C110845:AN 238; D000728:Androgens; D003603:Cytotoxins; D004337:Drug Carriers; D011758:Pyrroles; D013004:Somatostatin; D004317:Doxorubicin; C053408:RC 121; D015282:Octreotide