Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone

Kovács, Magdolna; Schally, Andrew V.; Nagy, Attila; Koppán, Miklós; Groot, Kate

doi:10.1073/pnas.94.4.1420

Cited by 49 publications

(42 citation statements)

References 27 publications

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“…Twenty-four hours after a long-term exposure (30 min) of the pituitary cells to the cytotoxic conjugate in vitro, no permanent damage of the pituitary somatotrope function was observed (data not shown). This finding is in agreement with our previous findings that the pituitary gonadotrope cells fully recover from the effects of long-term exposure to cytotoxic LH-RH conjugate (AN-207) containing 2-pyrrolino-DOX (41).…”

Section: Discussionsupporting

confidence: 83%

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

Nagy

Schally

Halmos

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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133

104

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Section: Discussionsupporting

confidence: 83%

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

Nagy

Schally

Halmos

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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133

104

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“…The damage inflicted by cytotoxic analogs to pituitary cells secreting LH, follicle-stimulating hormone, and GH would not be deleterious to the cancer patient since hypophysectomy has been used for treatment of some cancers (23). These studies indicate that cytotoxic LHRH analogs such as AN-207 have a selective and transient effect on LH cells but not on GH and prolactin cells while cytotoxic radical AN-201 non-selectively damages the pituitary cells (102). A possible damage to other cells, e.g.…”

Section: Cytotoxic Analogs Of Somatostatinmentioning

confidence: 99%

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

Schally

Nagy²

1999

European Journal of Endocrinology

266

228

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In view of non-specific toxicity of most chemotherapeutic agents against normal cells, the development of targeted chemotherapy is warranted. Efficient targeting of chemotherapeutic drugs to the cancerous area could be of great benefit for patients with advanced or metastatic tumors. Targeted cytotoxic peptide conjugates are hybrid molecules composed of a peptide carrier which binds to receptors on tumors and a cytotoxic moiety. New cytotoxic analogs of LHRH, AN-152 in which doxorubicin (DOX) is linked to ]LHRH, and AN-207 which consists of 2-pyrrolino-DOX (AN-201) coupled to the same carrier, show high-affinity binding and are much less toxic and more effective in vivo than their respective radicals in inhibiting tumor growth in LHRH receptor-positive models of human ovarian, mammary, or prostatic cancer. These results suggest that targeted cytotoxic LHRH analogs such as AN-207 could be considered for treatment of these cancers. The presence of receptors for bombesinlike peptides on a wide variety of tumors prompted us to use some of our bombesin/gastrin-releasing peptide antagonists as carrier molecules. Cytotoxic bombesin analogs, such as AN-215 containing AN-201, might find application in the treatment of small cell lung carcinoma (SCLC), and colorectal, gastric, pancreatic, mammary, and prostatic cancers. Since somatostatin receptors are found in various human neoplasms and the receptor subtypes to which octapeptide analogs bind with high affinity have been identified, we synthesized several cytotoxic somatostatin analogs including AN-162 and AN-238 containing DOX and 2-pyrrolino-DOX respectively, linked to octapeptide RC-121. Cytotoxic somatostatin analog AN-238 efficaciously inhibits growth of human breast or prostate cancers expressing somatostatin receptors-2 and -5 and can be used for receptor-targeted chemotherapy. Cytotoxic somatostatin analogs might also find applications for the therapy of human pancreatic, colorectal, and gastric cancer as well as brain tumors and non-SCLC. Cytotoxic compounds linked to analogs of hormonal peptides like LHRH, bombesin, and somatostatin that can be targeted to certain tumors possessing receptors for those peptides could be an important addition to oncological armamentarium.

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“…These results are consistent with the findings on the effects of AN-207 on the stimulated release of pituitary hormones. 28 Two weeks after the administration of AN-207, a full recovery of the pituitary was demonstrated, whereas AN-201 caused a longer lasting but reversible, nonselective damage. 28 We showed previously that chemotherapy targeted to LH-RH receptors produces superior tumor inhibition and lower toxicity than treatment with unconjugated cytotoxic radicals in mice with estrogendependent and estrogen-independent MXT mouse mammary tumors, 5,6,18 nude mice bearing human ovarian carcinomas, 14 and rats with Dunning prostate tumors.…”

Section: Discussionmentioning

confidence: 99%

“…28 Two weeks after the administration of AN-207, a full recovery of the pituitary was demonstrated, whereas AN-201 caused a longer lasting but reversible, nonselective damage. 28 We showed previously that chemotherapy targeted to LH-RH receptors produces superior tumor inhibition and lower toxicity than treatment with unconjugated cytotoxic radicals in mice with estrogendependent and estrogen-independent MXT mouse mammary tumors, 5,6,18 nude mice bearing human ovarian carcinomas, 14 and rats with Dunning prostate tumors. 13,15 The excellent responses of MX-1 human breast carcinomas to therapy with AN-207 reported herein provide more examples of the effectiveness of chemotherapy targeted to tumors that express receptors for LH-RH.…”

Section: Discussionmentioning

confidence: 99%

Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone-releasing hormone, AN-207

Kahán

Nagy

Schally

et al. 1999

Cancer

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Recovery of pituitary function after treatment with a targeted cytotoxic analog of luteinizing hormone-releasing hormone

Cited by 49 publications

References 27 publications

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

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

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

Complete regression of MX-1 human breast carcinoma xenografts after targeted chemotherapy with a cytotoxic analog of luteinizing hormone-releasing hormone, AN-207

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