We developed a powerful cytotoxic analogue of
bombesin AN-215, in which the
bombesin (BN)-like carrier
peptide is conjugated to 2-pyrrolino
doxorubicin (AN-201). Human
prostate cancers express high levels of receptors for BN/
gastrin releasing peptide (GRP) that can be used for targeted
chemotherapy. The effects of targeted
chemotherapy with cytotoxic BN analogue
AN-215 were evaluated in nude mice bearing subcutaneous xenografts of DU-145, LuCaP-35, MDA-PCa-2b and intraosseous implants of C4-2 human
prostate cancers. Intraosseous growth of C4-2
tumors was monitored by serum PSA. BN/GRP receptors were evaluated by 125I-[Tyr4]BN binding assays and RT-PCR. The effects of
AN-215 on apoptosis and cell proliferation were followed by histology, and the expression of Bcl-2 and
Bax protein was determined by Western blot analysis. Targeted analog
AN-215 significantly inhibited growth of subcutaneously implanted DU-145, LuCaP-35 and MDA-PCa-2b
prostate cancers by 81% to 91% compared to controls, while cytotoxic radical
AN-201 was less effective and more toxic. Serum PSA levels of mice bearing intraosseous C4-2 prostate
tumors were significantly reduced. In LuCaP-35
tumors administration of BN antagonist
RC-3095 prior to
AN-215 blocked the receptors for BN/GRP and inhibited the effects of
AN-215. High affinity receptors for BN/GRP and their m-
RNA were detected on membranes of all 4
tumor models.
Therapy with
AN-215, but not with
AN-201, decreased the ratio of Bcl-2/Bax in DU-145 and the expression of antiapoptotic Bcl-2 in LuCaP-35
tumors. The presence of BN/GRP receptors on primary and metastatic
prostate cancers makes possible targeted
chemotherapy with
AN-215 for the treatment of this
malignancy.