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
|