Design, synthesis, and
            <i>in vitro</i>
            evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin

Nagy, Attila; Armatis, Patricia; Cai, Ren; Szepesházi, Karoly; Halmos, Gábor; Schally, Andrew V.

doi:10.1073/pnas.94.2.652

Cited by 92 publications

(99 citation statements)

References 35 publications

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“…Targeting of antineoplastic agents to cancer cells by linking them to a ligand with high affinity for tumour cells should improve tumour growth inhibition and decrease peripheral toxicity . The presence of high affinity receptors for bombesin (BN)-like peptides on a wide variety of tumours prompted us to employ some of our powerful BN/gastrin releasing peptide (GRP) antagonists as carrier molecules for targeting cytotoxic agents to tumour cells (Nagy et al, 1997). One of these cytotoxic BN conjugates, AN-215 (Nagy et al, 1997) consists of a potent cytotoxic derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201) (Nagy et al, 1996), covalently linked through a glutaric acid spacer to the amino terminal of Gln-Trp-Ala-Val-Gly-His-Leu-c-Leu-NH 2, a BN-like peptide carrier (Nagy et al, 1997).…”

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“…The presence of high affinity receptors for bombesin (BN)-like peptides on a wide variety of tumours prompted us to employ some of our powerful BN/gastrin releasing peptide (GRP) antagonists as carrier molecules for targeting cytotoxic agents to tumour cells (Nagy et al, 1997). One of these cytotoxic BN conjugates, AN-215 (Nagy et al, 1997) consists of a potent cytotoxic derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201) (Nagy et al, 1996), covalently linked through a glutaric acid spacer to the amino terminal of Gln-Trp-Ala-Val-Gly-His-Leu-c-Leu-NH 2, a BN-like peptide carrier (Nagy et al, 1997). AN-215 displays high affinity to BN receptors on Swiss 3T3 fibroblasts and retains the antiproliferative effect of its cytotoxic moiety (Nagy et al, 1997).…”

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confidence: 99%

“…One of these cytotoxic BN conjugates, AN-215 (Nagy et al, 1997) consists of a potent cytotoxic derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201) (Nagy et al, 1996), covalently linked through a glutaric acid spacer to the amino terminal of Gln-Trp-Ala-Val-Gly-His-Leu-c-Leu-NH 2, a BN-like peptide carrier (Nagy et al, 1997). AN-215 displays high affinity to BN receptors on Swiss 3T3 fibroblasts and retains the antiproliferative effect of its cytotoxic moiety (Nagy et al, 1997). This cytotoxic conjugate was shown to effectively inhibit BN receptor-positive neoplasms, including H-69 human small-cell lung carcinoma (Kiaris et al, 1999a) and PC-3 human androgenindependent prostate cancer .…”

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confidence: 99%

“…of BN-like carrier analogue Gln-Trp-Ala-Val-Gly-His-Leu-c(CH 2 -NH)-Leu-NH 2 as described (Nagy et al, 1997). GRP(14-27), cytotoxic radical AN-201 (Nagy et al, 1996) and BN/GRP antagonist RC-3095 [D-Tpi 6 ,Leu 13 c(CH 2 NH)Leu 14 ]BN (6-14) (Radulovic et al, 1991) were also synthesised in our laboratory.…”

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

et al. 2002

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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.

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

et al. 2002

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“…13 Cytotoxic hybrids consisting of BN/GRP analogs conjugated to a cytotoxic radical and designed for targeting to prostate cancer and other neoplasms that express high percentage of BN receptors have been synthesized. 14 One of these analogs, AN-215, containing a potent derivative of doxorubicin (AN-201), 15 was made by coupling 2-pyrrolinodoxorubicin through hemiglutaric acid to the amino terminus of BN/GRP carrier analog RC-3095 [Gln-Trp-Ala-Val-GlyHis-Leu-W(CH 2 -NH)-Leu-NH 2 ]. AN-215 displays high affinity binding to BN receptors and retains the antiproliferative activity of its cytotoxic moiety 14,16 and has been shown to inhibit growth of experimental human prostate cancer in nude mice.…”

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Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN‐215) and a bombesin antagonist (RC‐3095)

Sotomayor

Muñoz-Moreno

Carmena

et al. 2010

Intl Journal of Cancer

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Bombesin (BN) and gastrin-releasing peptide (GRP) have been shown to stimulate the growth of human prostate cancer in vivo and in vitro by mechanisms initiated by binding of the peptide to BN/GRP receptor (GRPR). GRPR is overexpressed in a variety of human cancers, including human prostatic carcinoma. This led us to evaluate the effectiveness of blocking GRPR and of chemotherapy targeted to GRPR in androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cells, which exhibit different features of disease progression. Thus, we used a cytotoxic BN/GRP analog, AN-215, consisting of 2-pyrrolinodoxorubicin (AN-201) linked to BN-like carrier peptide, and a BN/GRP receptor antagonist, RC-3095. Semiquantitative RT-PCR and Western blotting revealed that mRNA and protein levels for GRPR increased in prostate cancer cells as compared with nonneoplastic RWPE-1 cells. Immunofluorocytochemistry and Western blot assays revealed that AN-215 was the most effective analog decreasing both the expression of epidermal growth factor receptor family members and the activation of epidermal growth factor receptor and HER-2, which are associated to a poor prognosis. Furthermore, analogs targeted to BN/GRP receptors, AN-215 and RC-3095, blocked the effect of BN on cell growth in RWPE-1, LNCaP and PC-3 cells. These findings shed light on the mechanisms of action of these analogs and support the view that the use of AN-215 and RC-3095 for blocking BN/GRP receptors for targeted therapy may be of benefit for treatment of advanced prostate cancer.Prostate carcinoma is the most common malignancy in men and the second leading cause of death from cancer. 1 Hormonal therapies based on androgen deprivation provide only a remission of limited duration, and patients with androgen refractory prostate cancer have a very poor prognosis. Treatment of advanced or metastatic cancers is carried out mainly by chemotherapy, which can also be applied as adjuvant to surgery and/or radiotherapy. 2 However, cancer chemotherapy is restricted by the toxicity of the drugs, and a more selective delivery of the cytotoxic agents to the tumors and their metastases would allow a dose escalation and reduce the peripheral toxicity. Targeted chemotherapy represents a modern oncologic strategy that improves the effectiveness of cytotoxic drugs and decreases their peripheral toxicity. 3 Bombesin (BN)-like peptides, such as gastrin-releasing peptide (GRP) and neuromedin B, bind to their specific Gprotein-coupled receptors (GPCRs) on the cell surface of tumors. 4,5 Three receptor subtypes are found in mammalians: neuromedin B receptor subtype (BB1), GRP receptor subtype (GRPR subtype or BB2 subtype) and orphan receptor subtype (BB3). 6 BN-like peptides regulate the expression of multiple genes and intracellular signaling pathways, which together may enhance prostate cancer growth and metastasis. 7 High affinity receptors for BN/GRP and mRNA of the BN receptor subtype 2 have been found in androgen-dependent (LNCaP) and androgen-independent (PC-3 and DU-145) hum...

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Presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human prostate cancers

Sun¹,

et al. 2000

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Design, synthesis, and in vitro evaluation of cytotoxic analogs of bombesin-like peptides containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin

Cited by 92 publications

References 35 publications

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

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

Regulation of HER expression and transactivation in human prostate cancer cells by a targeted cytotoxic bombesin analog (AN‐215) and a bombesin antagonist (RC‐3095)

Presence of receptors for bombesin/gastrin-releasing peptide and mRNA for three receptor subtypes in human prostate cancers

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