Abstract
Cytotoxic luteinizing hormone-releasing hormone (LH-RH) analogs, AJ-004 (agonist [D-Lys6]LH-RH linked to methotrexate (MTX)), T-98 ([D-Lys6]LH-RH coupled to glutaryl-2-(hydroxymethyl)anthraquinone) (G-HMAQ) and T-121/B (antagonist containing two residues of G-HMAQ) were tested in female BDF1 mice bearing MXT ((3.2)/Ovex) estrogen-independent mammary tumors. All three cytotoxic LH-RH analogs, administered from Alzet Osmotic Minipumps for 3 weeks, produced a significant inhibition of tumor growth. The effects of T-98 and T-121/B were superior to those obtained by treatment with equimolar doses of cytotoxic moiety anthraquinone or the LH-RH carrier alone. We assume that cytotoxic LH-RH analogs have a combined hormonal and cytotoxic activity with a reduced toxicity after administration in vivo. This is the first demonstration of in vivo tumor inhibition by targeted LH-RH analogs bearing cytotoxic radicals.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Anthraquinones / administration & dosage
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Anthraquinones / pharmacology*
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Binding Sites
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Body Weight / drug effects
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Cell Division / drug effects
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Female
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Gonadotropin-Releasing Hormone / administration & dosage
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Gonadotropin-Releasing Hormone / analogs & derivatives*
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Gonadotropin-Releasing Hormone / antagonists & inhibitors
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Gonadotropin-Releasing Hormone / pharmacology
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Growth Hormone / blood
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Kinetics
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Luteinizing Hormone / blood
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Mammary Neoplasms, Experimental / drug therapy*
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Mammary Neoplasms, Experimental / pathology
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Methotrexate / administration & dosage
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Methotrexate / pharmacology*
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Mice
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Mice, Inbred Strains
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Molecular Sequence Data
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Ovary / anatomy & histology
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Receptors, LH / metabolism
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Triptorelin Pamoate
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Uterus / anatomy & histology
Substances
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Anthraquinones
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Receptors, LH
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Triptorelin Pamoate
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glutaryl-2-(hydroxymethyl)anthraquinone
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Gonadotropin-Releasing Hormone
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Luteinizing Hormone
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Growth Hormone
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Methotrexate