This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krebs, L. J. Articles by Liebow, C. Search for Related Content PubMed PubMed Citation Articles by Krebs, L. J. Articles by Liebow, C.

Regulation of Targeted Chemotherapy with Cytotoxic Lutenizing Hormone-releasing Hormone Analogue by Epidermal Growth Factor¹

Department of Chemistry, Institute for Lasers, Photonics, and Biophotonics, State University of New York, Buffalo, New York 14260 [L. J. K., X. W., H. E. P., E. J. B., P. N. P., C. L.]; Departments of Physiology and Biophysics [L. J. K., C. L.] and Oral Biology [L. J. K.], State University of New York, Buffalo, New York 14214; and Veterans Affairs Medical Center and Tulane University School of Medicine, New Orleans, Louisiana 70112 [A. V. S., A. N.]

Targeting chemotherapy selectively to cancers can reduce the toxic side effects. AN-152, a conjugate of doxorubicin and [D-Lys⁶]-luteinizing hormone-releasing hormone (LH-RH), is more potent against LH-RH receptor-bearing cancers and produces less peripheral toxicity than doxorubicin. Many cancers, e.g., 50% of breast cancers, but few normal tissues express these receptors, providing a selective target for this cytotoxic conjugate. In this study, the effectiveness of AN-152 was heightened by receptor up-regulation. The cytotoxic effect of AN-152 can be regulated by the number of active LH-RH receptors on cancer cells. LH-RH receptor-positive (MCF-7) and -negative (UCI-107) cancer cells were treated with epidermal growth factor (EGF) or the somatostatin analogue, RC-160. EGF and RC-160 have been shown previously to regulate LH-RH receptors through phosphorylation. The effect of receptor regulation, by hormone exposure, on the cytotoxicity of AN-152 and doxorubicin and on the cellular uptake of AN-152, [D-Lys⁶]LH-RH, or doxorubicin was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and by two-photon laser scanning microscopy. The results demonstrated that the cellular entry of the conjugate was: (a) specific for cancers with LH-RH receptors; (b) up-regulated by EGF; (c) down-regulated by RC-160; and (d) the cytotoxicity of the AN-152 paralleled the efficiency of entry. This study illustrates the potential use of receptor regulation for increasing the efficacy of chemotherapeutic approaches that are directed to cell surface receptors.

This article has been cited by other articles:

				A. Nagy and A. V. Schally Targeting of Cytotoxic Luteinizing Hormone-Releasing Hormone Analogs to Breast, Ovarian, Endometrial, and Prostate Cancers Biol Reprod, November 1, 2005; 73(5): 851 - 859. [Abstract] [Full Text] [PDF]

				I. Roy, T. Y. Ohulchanskyy, D. J. Bharali, H. E. Pudavar, R. A. Mistretta, N. Kaur, and P. N. Prasad Optical tracking of organically modified silica nanoparticles as DNA carriers: A nonviral, nanomedicine approach for gene delivery PNAS, January 11, 2005; 102(2): 279 - 284. [Abstract] [Full Text] [PDF]

				M. Letsch, A. V. Schally, K. Szepeshazi, G. Halmos, and A. Nagy Preclinical Evaluation of Targeted Cytotoxic Luteinizing Hormone-Releasing Hormone Analogue AN-152 in Androgen-Sensitive and Insensitive Prostate Cancers Clin. Cancer Res., October 1, 2003; 9(12): 4505 - 4513. [Abstract] [Full Text] [PDF]

				A. M. Bajo, A. V. Schally, G. Halmos, and A. Nagy Targeted Doxorubicin-containing Luteinizing Hormone-releasing Hormone Analogue AN-152 Inhibits the Growth of Doxorubicin-resistant MX-1 Human Breast Cancers Clin. Cancer Res., September 1, 2003; 9(10): 3742 - 3748. [Abstract] [Full Text] [PDF]

				J. C. Reubi Peptide Receptors as Molecular Targets for Cancer Diagnosis and Therapy Endocr. Rev., August 1, 2003; 24(4): 389 - 427. [Abstract] [Full Text] [PDF]