Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Schally, Andrew V.; Nagy, Attila

doi:10.1530/eje.0.1410001

Cited by 264 publications

(243 citation statements)

References 94 publications

(150 reference statements)

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“…6,20,21 GnRH analogs with a cytotoxic agent covalently linked to a GnRH analog have been developed. 22 Furthermore, GnRH antagonists are used in cancer therapy. 6,15 The demonstration of GnRH-R I and II expression in endometrial stromal sarcomas may be a rationale for a clinical study of GnRH analogs in the treatment of women with endometrial stromal sarcomas.…”

Section: Discussionmentioning

confidence: 99%

Gonadotropin-releasing hormone receptor expression in endometrial stromal sarcomas: an immunohistochemical study

2005

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Gonadotropin-releasing hormone and its receptors have been identified in several human malignancies. We evaluated gonadotropin-releasing hormone receptor expression in 30 primary and recurrent endometrial stromal sarcomas. Archival formalin-fixed and paraffin-embedded material was analyzed immunohistochemically with antisera to gonadotropin-releasing hormone receptor type I and gonadotropin-releasing hormone receptor type II using the peroxidase-antiperoxidase method. Gonadotropin-releasing hormone receptor types I and II were demonstrated in most primary endometrial stromal sarcomas in varying intensity and percentage (range, 10-100%). The staining pattern was either diffuse cytoplasmic or granular/vesicular in perinuclear distribution. Recurrences stained stronger than primary tumors. The demonstration of gonadotropin-releasing hormone receptors I and II expression in endometrial stromal sarcomas may be a rationale for a clinical study of gonadotropin-releasing hormone analogs in the treatment of women with endometrial stromal sarcomas.

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Section: Discussionmentioning

confidence: 99%

Gonadotropin-releasing hormone receptor expression in endometrial stromal sarcomas: an immunohistochemical study

2005

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“…This cytotoxic analog consists of doxorubicin (DOX) conjugated at its 14-OH group, through a glutaric acid spacer, to the epsilon-amino group of the D-Lys side chain of the carrier peptide. The drug enters the cell specifically by means of receptor mediated endocytosis [36]. This compound, when compared to unconjugated cytotoxic compounds, acts selectively on those cells that express this receptor and hence exerts many fewer side effects on normal cells, that do not express the receptor.…”

Section: Discussionmentioning

confidence: 99%

LHRH receptor expression in sarcomas of bone and soft tissue

Deivaraju¹,

Temple²,

Block³

et al. 2016

Hormone Molecular Biology and Clinical Investigation

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Aim: Luteinizing hormone releasing hormone (LHRH) is a neurohormone, secreted by the hypothalamus, which regulates the secretion of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the pituitary. LHRH acts by binding to receptors located in the pituitary gland. These receptors (LHRH receptors) have also been found in the cytoplasm of many tumor cells that involve both the reproductive and non-reproductive organs. These receptors have been demonstrated in prostate and breast cancers, endometrial carcinomas, renal cell carcinoma, lymphoma, carcinoma of liver, pancreas and skin. So far, the expression of LHRH receptors on sarcomas (i.e. malignant tumors of mesenchymal origin) has not been studied, except for endometrial sarcomas. It has also been demonstrated that both LHRH agonists and antagonists can down-regulate these receptors and thus inhibit these tumor cells. Another major therapeutic implication is that these receptors can be targeted specifically by peptides conjugated to anti-cancer drugs. The purpose of this study was to determine if LHRH receptors are expressed in primary and/or metastatic sarcomas of human origin. Methods: We looked at LHRH receptor expression in 38 consecutive sarcoma specimens, using immunohistochemistry. The specimens were either from office biopsy or from resected tumor; these were confirmed as sarcomas by histopathological examination. The receptor staining characteristics and the staining intensity were also documented. The pattern of staining was classified either as "focal or diffuse staining of the cytoplasm" and the intensity of staining was graded on a scale from 1+ to 4+. Results: Positive receptor staining was seen in 25 of the 38 (66%) specimens. Twelve of the specimens stained diffusely and 13 had focally positive staining. Three tumors had 1+ staining, 10 had 2+ staining, six had 3+ staining, and six tumors had 4+ staining. The tumors included undifferentiated pleomorphic sarcoma, synovial sarcoma, osteosarcoma, myofibroblastic sarcoma, myxofibrosarcoma, liposarcoma, dermatofibrosarcoma protuberans, metastatic chondrosarcoma and chordoma. Conclusion: Sarcomas express LHRH receptors with a varying incidence and degree. Our study suggests that those sarcomas that are LHRH receptor positive could potentially be treated with targeted chemotherapy.

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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%

“…Because somatostatin receptors are widely distributed in the gastrointestinal tract and other tissues, 11,22,29 concerns were raised that therapy with radionuclide somatostatin analogues or AN-238 may produce some side effects. However, in early studies with radiolabeled somatostatin analogues, no or only low-grade toxicity was observed in patients at doses resulting in objective responses.…”

Section: Discussionmentioning

confidence: 99%

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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Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors

Cited by 264 publications

References 94 publications

Gonadotropin-releasing hormone receptor expression in endometrial stromal sarcomas: an immunohistochemical study

Gonadotropin-releasing hormone receptor expression in endometrial stromal sarcomas: an immunohistochemical study

LHRH receptor expression in sarcomas of bone and soft tissue

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

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