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

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.

• Authors: L J Krebs, X Wang, H E Pudavar, E J Bergey, A V Schally, A Nagy, P N Prasad, C Liebow
• Journal: Cancer research (Cancer Res) Vol. 60 Issue 15 Pg. 4194-9 (Aug 01 2000) ISSN: 0008-5472 [Print] United States
• PMID: 10945629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Drug Carriers
• Fluorescent Dyes
• Receptors, LHRH
• LHRH, lysine(6)-doxorubicin
• vapreotide
• Gonadotropin-Releasing Hormone
• Somatostatin
• LHRH, Lys(6)-
• Epidermal Growth Factor
• Doxorubicin

Topics

• Antineoplastic Agents (pharmacokinetics, toxicity)
• Breast Neoplasms (drug therapy, metabolism)
• Cell Membrane (metabolism)
• Cell Nucleus (metabolism)
• Cytoplasm (metabolism)
• Doxorubicin (analogs & derivatives, pharmacokinetics, toxicity)
• Drug Carriers
• Drug Screening Assays, Antitumor
• Drug Synergism
• Epidermal Growth Factor (pharmacology)
• Fluorescent Dyes
• Gonadotropin-Releasing Hormone (analogs & derivatives, pharmacokinetics, toxicity)
• Humans
• Microscopy, Fluorescence
• Receptors, LHRH (metabolism)
• Somatostatin (analogs & derivatives, pharmacology)
• Tumor Cells, Cultured