Targeted doxorubicin-containing luteinizing hormone-releasing hormone analogue AN-152 inhibits the growth of doxorubicin-resistant MX-1 human breast cancers.
OBJECTIVE
The receptors for luteinizing hormone-releasing hormone receptor (LHRH-R) are found in >50% of human breast cancers. Doxorubicin (DOX) was linked to [D-Lys(6)]LHRH to form a cytotoxic conjugate, AN-152, which can be targeted to tumor cells expressing LHRH-R. We evaluated the effects of AN-152 on the estrogen-independent, DOX-resistant human mammary carcinoma line MX-1, xenografted into nude mice.


METHODS
Nude mice bearing MX-1 tumors were administered five i.v. injections of AN-152 or DOX at doses equivalent to 3 mg/kg DOX. Tumor growth was followed, and changes in the expression of LHRH-R on tumors were evaluated by radioreceptor assays, reverse transcription-PCR, and Western blotting. The effects of AN-152 on the expression of human epidermal growth factor receptor (HER)-2 were investigated. Because LHRH-R are coupled to various G proteins, which are involved in mitogenic signaling, we determined the outcome of treatment with AN-152 on the levels of mRNA for different G proteins.


RESULTS
Treatment with AN-152 significantly (P < 0.05) decreased the final tumor volume to 978.56 +/- 176.85 mm(3), compared with the control tumors, which measured 2837.38 +/- 515.38 mm(3). Tumor doubling time was likewise significantly (P < 0.05) extended by AN-152 to 12.01 +/- 1.99 days from 6.45 +/- 0.36 days for the controls. Therapy with AN-152, but not with DOX, resulted in a significant decrease of LHRH-R levels on MX-1 tumors. The expression of mRNAs for HER-2, HER-3, Galpha(i2), and Galpha(11) and the levels of HER-2 and HER-3 proteins were also significantly reduced by AN-152.


CONCLUSIONS
Cytotoxic LHRH analogue AN-152 could be considered for targeted chemotherapy of DOX-resistant breast cancers expressing LHRH-R.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D006801:Humans; D007986:Luteinizing Hormone / Q000097:blood; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C080883:LHRH, lysine(6)-doxorubicin