Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely  potent derivative, 2-pyrrolinodoxorubicin

Nagy, Attila; Schally, Andrew V.; Halmos, Gábor; Armatis, Patricia; Cai, Renzhi; Csernus, Valér; Kovács, Magdolna; Koppán, Miklós; Szepesházi, Karoly; Kahán, Zsuzsanna

doi:10.1073/pnas.95.4.1794

Cited by 133 publications

(109 citation statements)

References 41 publications

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“…7,8,17,22 The anti-CD20 MAb rituximab and the radiolabeled anti-CD20 antibodies Zevalin and Bexxar have shown promising clinical results in the treatment of NHL. 5,6 However, MAbs are large molecules, and it may be assumed that smaller ligands, like peptides, penetrate more easily into tumor tissue and are excreted faster if not bound to their receptor, which would decrease toxic side effects.…”

Section: Discussionmentioning

confidence: 99%

“…18,19 AN-238 was made by coupling AN-201-14-O-hemiglutarate to the NH 2 terminus of [Lys-(N-(9-fluorenyl)methoxycarbonyl) 5 ]RC-121, followed by deprotection and purification. 17 For i.v. injection, compounds were dissolved in 20 l of 0.01 N aqueous acetic acid and diluted with 5% (w/v) aqueous D-mannitol solution (Sigma, St. Louis, MO).…”

Section: Peptides and Cytotoxic Agentsmentioning

confidence: 99%

“…17 AN-238 consists of the carrier somatostatin octapeptide RC-121 linked covalently to a highly potent derivate of DOX, AN-201. 18 This analogue fully retains the cytotoxic activity of the radical and binds with high affinity to somatostatin receptor subtypes sst 2 and sst 5 and with medium affinity to subtype sst 3 .…”

mentioning

confidence: 99%

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Growth inhibition of experimental non‐Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN‐238

Keller¹,

Engel

Schally

et al. 2005

Intl Journal of Cancer

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Key words: targeted chemotherapy; non-Hodgkin's lymphoma; somatostatin receptor; NHL is the most frequently diagnosed hematologic malignancy and ranks as the sixth most common cause of cancer-related deaths in the United States. 1,2 Over the past 50 years, an increased incidence of NHL has been reported, with an estimated 54,370 new cases in 2004. 1,2 Depending on the classification, the treatment of choice can include surgical intervention, conventional chemotherapy, radiotherapy or a combination of these. 2,3 However, patients who have advanced-stage NHL with tumors Ͼ10 cm in diameter and more than one extranodal lesion face a dismal prognosis, with a 5-year survival rate of 26%. 3 These findings emphasize the importance of developing effective therapies. 3 The discovery of specific surface antigens in various human cancers led to the development of targeted antitumor agents like MAbs. 4 These antibodies are used as single drugs or attached to radioisotopes and toxins. In the case of NHL, the anti-CD20 MAb rituximab (Rituxan) and the radiolabeled anti-CD20 antibodies Yttrium 90 ibritumomab tiuxetan (Zevalin) and 131 I tositumomab (Bexxar) were approved by the U.S. Food and Drug Administration and yielded promising clinical results. 5,6 In addition, receptors for some peptide hormones are found in relatively high concentrations on many cancer types, providing another option for targeted therapy with radiolabeled peptide hormones or cytotoxic peptide conjugates. 7-9 Expression of somatostatin receptors was found in 70 -100% of surgically removed NHL specimens of low-, intermediate-and high-grade malignancy. 10 Consequently, in several clinical studies, radiolabeled somatostatin analogues such as [ 111 In-DTPA-D-Phe 1 ]-octreotide ( 111 In-pentetreotide, OctreoScan) were used to detect lymphomatous lesions in patients with NHL. 11-14 Based on these results, the "straight" somatostatin analogue octreotide, which can decrease the growth of certain somatostatin receptor-positive cancers, was used in patients with NHL and showed some antitumor activity in 2 phase II trials when administered as a single agent or in combination therapy. 15,16 These studies [11][12][13][14][15][16] indicate that somatostatin receptors might be utilized for the targeted therapy of NHL based on radionuclide or cytotoxic somatostatin analogues.Previously, we developed a cytotoxic somatostatin analogue, AN-238, for the targeted therapy of somatostatin receptor-positive cancers. 17 AN-238 consists of the carrier somatostatin octapeptide RC-121 linked covalently to a highly potent derivate of DOX, This analogue fully retains the cytotoxic activity of the radical and binds with high affinity to somatostatin receptor subtypes sst 2 and sst 5 and with medium affinity to subtype sst 3 . AN-238 significantly inhibits the growth of various tumors that express somatostatin receptors (subtypes 2, 3 and 5). 7,8 Here, we evaluated the antitumor effects and toxicity of cytotoxic somatostatin analogue AN-238 on 2 different human NHL cell lines xenograf...

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Section: Discussionmentioning

confidence: 99%

Section: Peptides and Cytotoxic Agentsmentioning

confidence: 99%

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Growth inhibition of experimental non‐Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN‐238

Keller¹,

Engel

Schally

et al. 2005

Intl Journal of Cancer

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“…Monoclonal antibodies [5][6][7][8], polyunsaturated fatty acids [9,10], folic acid [11][12][13], aptamers [14,15], transferrin [16], oligopeptides [17] and hyaluronic acid [18] have widely been used as tumour-specific agents to design tumour-targeting drug conjugates. Although vitamins are essential to all living organisms for their existence, rapidly dividing cancer cells require certain vitamins to sustain their rapid growth [19,20].…”

Section: Introductionmentioning

confidence: 99%

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Saha

Majumdar

Hussain

et al. 2013

Phil. Trans. R. Soc. A.

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Iron(III) complexes [FeL(B)] ( 1 – 4 ) of a tetradentate phenolate-based ligand (H 3 L) and biotin-conjugated dipyridophenazine bases (B), viz. 7-aminodipyrido [3,2- a :2′,3′- c ]-phenazine (dppza in 1 ), ( N -dipyrido[3,2- a :2′,3′- c ]-phenazino)amidobiotin (dppzNB in 2 ), dipyrido [3,2- a :2′,3′- c ]-phenazine-11-carboxylic acid (dppzc in 3 ) and 2-((2-biotinamido)ethyl) amido-dipyrido[3,2- a :2′,3′- c ]-phenazine (dppzCB in 4 ) are prepared, characterized and their interaction with streptavidin and DNA and their photocytotoxicity and cellular uptake in various cells studied. The high-spin iron(III) complexes display Fe(III)/Fe(II) redox couple near −0.7 V versus saturated calomel electrode in dimethyl sulfoxide–0.1 M tetrabutylammonium perchlorate. The complexes show non-specific interaction with DNA as determined from the binding studies. Complexes with appended biotin moiety show similar binding to streptavidin as that of free biotin, suggesting biotin conjugation to dppz does not cause any loss in its binding affinity to streptavidin. The photocytotoxicity of the complexes is tested in HepG2, HeLa and HEK293 cell lines. Complex 2 shows higher photocytotoxicity in HepG2 cells than in HeLa or HEK293, forming reactive oxygen species. This effect is attributed to the presence of overexpressed sodium-dependent multi-vitamin transporters in HepG2 cells. Microscopic studies in HepG2 cells show internalization of the biotin complexes 2 and 4 essentially occurring by receptor-mediated endocytosis, which is similar to that of native biotin and biotin fluorescein isothiocyanate conjugate.

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“…Several approaches have been developed in order to deliver specifically Doxorubicin to tumor cells using monoclonal antibodies (mAbs) or small peptides as carrier molecules (Arap et al, 1998;Nagy et al, 1998;King et al, 1999;Stan et al, 1999;Garsky et al, 2001;Langer et al, 2001). Targeted chemotherapy couples a drug to a carrier molecule (ligand), and depends on the ability of the ligand to bind selectively to the target tumor cells in such a way that it may increase the drug concentration near the tumor while decreasing systemic toxicity.…”

Section: Introductionmentioning

confidence: 99%

Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity

Guillemard

Saragovi

2004

Oncogene

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Synthesis and biological evaluation of cytotoxic analogs of somatostatin containing doxorubicin or its intensely potent derivative, 2-pyrrolinodoxorubicin

Abstract: To create cytotoxic hybrid analogs of somatostatin (

Cited by 133 publications

References 41 publications

Growth inhibition of experimental non‐Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN‐238

Growth inhibition of experimental non‐Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue AN‐238

Biotin-conjugated tumour-targeting photocytotoxic iron(III) complexes

Prodrug chemotherapeutics bypass p-glycoprotein resistance and kill tumors in vivo with high efficacy and target-dependent selectivity

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