Effect of a cytotoxic analog of LH-RH (T-98) on the growth of estrogen-dependent MXT mouse mammary cancers: correlations between growth characteristics and EGF receptor content of tumors.

Abstract

Female BDF mice bearing estrogen-dependent MXT mouse mammary cancers were treated for 4 weeks with a cytotoxic analog of luteinizing hormone-releasing hormone (LH-RH). T-98 (agonist [D-Lys6]LH-RH linked to glutaryl-2(hydroxymethyl)anthraquinone). The effects of T-98 were compared to those of equimolar amounts of the cytotoxic moiety 2-(hydroxymethyl)anthraquinone hemiglutarate (G-HMAQ) and carrier LH-RH agonist [D-Lys6]LH-RH. Both T-98 and [D-Lys6]LH-RH significantly inhibited the growth of MXT cancers, but G-HMAQ had only a minor non-significant effect. Cytotoxic analog T-98 and the carrier [D-Lys6]LH-RH had similar inhibitory hormonal activities on the pituitary-gonadal axis, but T-98 caused a larger reduction in tumor volume and decreased proliferation characteristics such as mitotic activity and AgNOR numbers in tumor cells to a greater extent than the carrier. Tumor inhibition by T-98, [D-Lys6]LH-RH, and ovariectomy was connected with a significant decrease in binding capacity of EGF receptors in tumor cell membranes. The concentration of EGF receptors remained high in tumors that continued to enlarge in spite of treatment and in all control untreated tumors, even those of small size. Thus, the changes in EGF receptors are likely to be the result of the therapy. Treatment with T-98 caused a greater reduction in the binding capacity of EGF receptors in tumors than [D-Lys6]LH-RH. This could explain the higher inhibitory effect of the cytotoxic analog on tumor growth. Since radiolabeled T-98 was shown to accumulate in MXT cancers 3 hours after a subcutaneous injection, this indicates that specific targeting might play a role in the antitumor effect exerted by this cytotoxic analog.

• Authors: K Szepeshazi, A V Schally, G Halmos, B Szoke, K Groot, A Nagy
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 40 Issue 2 Pg. 129-39 ( 1996) ISSN: 0167-6806 [Print] Netherlands
• PMID: 8879679 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anthraquinones
• Antineoplastic Agents, Hormonal
• Estrogens
• Iodine Radioisotopes
• LHRH, lysine(6)-glutaryl-2-(hydroxymethyl)anthraquinone
• Gonadotropin-Releasing Hormone
• Estradiol
• Luteinizing Hormone
• ErbB Receptors

Topics

• Animals
• Anthraquinones (pharmacokinetics, pharmacology)
• Antineoplastic Agents, Hormonal (pharmacokinetics, pharmacology)
• Cell Division (drug effects, physiology)
• ErbB Receptors (metabolism)
• Estradiol (blood)
• Estrogens (physiology)
• Female
• Gonadotropin-Releasing Hormone (analogs & derivatives, pharmacokinetics, pharmacology)
• Iodine Radioisotopes
• Luteinizing Hormone (blood)
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred Strains
• Neoplasms, Hormone-Dependent (drug therapy, metabolism, pathology)
• Tissue Distribution