Regulation of targeted chemotherapy with cytotoxic lutenizing hormone-releasing hormone analogue by epidermal growth factor.
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.
Krebs
L J
LJ
Department of Chemistry, Institute for Lasers, Photonics, and Biophotonics, State University of New York, Buffalo 14260, USA.
Wang
X
X
Pudavar
H E
HE
Bergey
E J
EJ
Schally
A V
AV
Nagy
A
A
Prasad
P N
PN
Liebow
C
C
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D004337:Drug Carriers; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005456:Fluorescent Dyes; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D008856:Microscopy, Fluorescence; D011966:Receptors, LHRH / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004337:Drug Carriers; D005456:Fluorescent Dyes; D011966:Receptors, LHRH; C080883:LHRH, lysine(6)-doxorubicin; C051458:vapreotide; D007987:Gonadotropin-Releasing Hormone; D013004:Somatostatin; C035029:LHRH, Lys(6)-; D004815:Epidermal Growth Factor; D004317:Doxorubicin