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

Abstract

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...

New Approaches to the Therapy of Various Tumors Based on Peptide Analogues

“…Nude mice bearing xenografts of RL and HT human NHL were treated with AN-238. AN-238 signifi cantly inhibited the growth of RL tumors and HT xenografts [62] . AN-238 could be considered for the treatment for patients with NHL.…”

“…Because somatostatin receptors are found in a high percentage of human non-Hodgkin ' s lymphomas (NHL), we evaluated the antitumor effect of AN-238 in two human NHL cell lines in vivo [62] . Nude mice bearing xenografts of RL and HT human NHL were treated with AN-238.…”

Loss of Somatostatin Receptor Subtype 2 in Prostate Cancer Is Linked to an Aggressive Cancer Phenotype, High Tumor Cell Proliferation and Predicts Early Metastatic and Biochemical Relapse

“…Several other therapeutic ligands of SSTR2 are currently available or under clinical testing, including long-acting formulations (lancreotide, vapreotide, seglitide and pasireotide/SOM230) [33], and chimeric molecules coupled with cytotoxic agents (e.g. AN-238, a doxorubicin/somatostatin conjugate, [34]). …”

“…Moreover, experimental treatment with the cytotoxic somatostatin analog AN-238 strongly inhibited tumor proliferation in a broad variety of SSTR2 positive cancer models such as Non-Hodgkin’s lymphoma [34], malignant melanoma [36], pheochromocytoma [37], endometrial [38], ovarian [39], colon [40] and gastric carcinomas [41] as well as small and non-small cell lung carcinoma [42], [43].…”

Ο Ρόλος Της Εκλυτικής Ορμόνης Της Αυξητικής Ορμόνης Στην Καρκινογένεση

“…Η αντίδραση αλυσιδωτής πολυμεράσης με χρήση του ενζύμου αντίστροφης μεταγραφάσης καθώς επίσης και μελέτες ανοσοαποτύπωσης κατά Western με αντίσωμα ειδικό για το SV1 έδειξαν την έκφραση του SV1 ποικιλία καρκίνων, όπως προστάτη (Halmos et al, 2002), παχέως εντέρου, γαστρικού, παγκρεατικού (Busto et al, 2002b) νεφρικού (Halmos et al, 2000), καρκίνο του μαστού (Barabutis et al, 2007;Chatzistamou et al, 2004), ωοθήκης και ενδομητρίου (Engel et al, 2005a). Επιπρόσθετα, το SV1 ανιχνεύτηκε σε οστικά σαρκώματα (Busto et al, 2002a), γλοιοβλαστώματα (Kanashiro et al, 2005) καθώς επίσης και λεμφώματα (Keller et al, 2005a;Keller et al, 2005b). (Csernus et al, 1999;Schally andVarga, 1999, 2006 (Jarrett, 2008;Rigas and Sun, 2008).…”