Effective treatment of experimental U-87MG human glioblastoma in nude mice with a targeted cytotoxic bombesin analogue, AN-215

Abstract

Some brain tumours, such as glioblastomas express high levels of receptors for bombesin/gastrin releasing peptide. We investigated whether bombesin/gastrin releasing peptide receptors found in glioblastoma cell lines can be utilised for targeting of a cytotoxic bombesin analogue, AN-215 consisting of a potent derivative of doxorubicin, 2-pyrrolino-doxorubicin (AN-201) linked to a bombesin-like peptide carrier. This study reports the effect of AN-215 on the growth of U-87MG human glioblastomas xenografted into nude mice. High affinity binding of AN-215 to U-87MG tumours was characterised by an IC 50 value of 4.0+0.1 nM, as determined by radioreceptor assays. mRNA analyses revealed the presence of mRNA for BN receptor subtypes 1 and 2. Treatment with AN-215 significantly (P50.05) extended tumour doubling time from 4.54+0.2 days to 8.18+1.8 days and inhibited tumour growth as demonstrated by a 69.6% reduction in final tumour volume (P50.001) and a 64.6% decrease in tumour weight as compared to controls. Cytotoxic radical AN-201 at the same dose was ineffective. The antitumour effect of AN-215 could be blocked by pretreatment with an excess of a bombesin antagonist, indicating that the action of this cytotoxic analogue is receptor-mediated. Our results suggest that patients with inoperable brain tumours such as malignant gliomas may benefit from targeted chemotherapy based on cytotoxic bombesin analogue AN-215.

Triple-negative breast cancers express receptors for growth hormone-releasing hormone (GHRH) and respond to GHRH antagonists with growth inhibition

“…Accordingly, the expression of mRNA for GHRH or its peptide product were detected in surgical specimens of human endometrial, ovarian, breast and prostatic cancers [27,31,32]. mRNAs encoding four splice variants (SV) of GHRH receptors and specific high affinity binding sites for GHRH and its antagonistic analogs have been identified in diverse cell lines and specimens of human cancers [19,20,24,25,28,29,31,[33][34][35][36]. These findings suggest that the direct antiproliferative action of GHRH antagonists could be exerted through the disruption of an autocrine/paracrine stimulatory loop formed by tumoral GHRH and its receptors on tumors [14,19,20,28,29,35,37,38].…”

Synthesis and Evaluation of Bombesin Derivatives on the Basis of Pan-Bombesin Peptides Labeled with Indium-111, Lutetium-177, and Yttrium-90 for Targeting Bombesin Receptor-Expressing Tumors

“…These findings provide a possibility to apply bombesin-like peptides as a vehicle for delivering cytotoxic drugs (23)(24)(25) into tumor cells. In addition, radiolabeling may allow us to diagnose and treat these tumors (10, 26 -37).…”

Specific Growth Rate versus Doubling Time for Quantitative Characterization of Tumor Growth Rate

“…Tumor growth rate is widely used for prognostic purposes and can quantify therapeutic effects of different treatment modalities (1)(2)(3)(4)(5)(6)(7)(8)(9). Tumor cells duplicate during cell cycle, which theoretically causes an exponential growth.…”