Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor

L. J. Krebs, X. Wang, H. E. Pudavar, E. J. Bergey, Andrew V Schally, A. Nagy, P. N. Prasad, C. Liebow

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)4194-4199
Number of pages6
JournalCancer Research
Volume60
Issue number15
StatePublished - Aug 31 2000
Externally publishedYes

Fingerprint

LHRH Receptors
Epidermal Growth Factor
Gonadotropin-Releasing Hormone
Drug Therapy
Doxorubicin
Neoplasms
Poisons
Cell Surface Receptors
Somatostatin
Photons
Confocal Microscopy
lysine(6)-doxorubicin LHRH
Up-Regulation
Phosphorylation
Hormones
Breast Neoplasms
vapreotide

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Krebs, L. J., Wang, X., Pudavar, H. E., Bergey, E. J., Schally, A. V., Nagy, A., ... Liebow, C. (2000). Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor. Cancer Research, 60(15), 4194-4199.

Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor. / Krebs, L. J.; Wang, X.; Pudavar, H. E.; Bergey, E. J.; Schally, Andrew V; Nagy, A.; Prasad, P. N.; Liebow, C.

In: Cancer Research, Vol. 60, No. 15, 31.08.2000, p. 4194-4199.

Research output: Contribution to journalArticle

Krebs, LJ, Wang, X, Pudavar, HE, Bergey, EJ, Schally, AV, Nagy, A, Prasad, PN & Liebow, C 2000, 'Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor', Cancer Research, vol. 60, no. 15, pp. 4194-4199.
Krebs, L. J. ; Wang, X. ; Pudavar, H. E. ; Bergey, E. J. ; Schally, Andrew V ; Nagy, A. ; Prasad, P. N. ; Liebow, C. / Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor. In: Cancer Research. 2000 ; Vol. 60, No. 15. pp. 4194-4199.
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