A novel design of targeted endocrine and cytokine therapy for breast cancer.
The aim of this study is to combine endocrine therapy [human prolactin (hPRL) antagonist, G129R] and immune therapy [interleukin 2 (IL2)] in the design of a fusion protein, G129R-IL2, to treat human breast cancer. This novel approach uses the specific interaction between the G129R and hPRL receptors (PRLRs), thus directly targeting the fusion protein to the malignant breast tissues that have previously been shown to contain high levels of PRLR. The localized bifunctional fusion protein is designed to block signal transduction induced by hPRL as well as to activate T lymphocytes near the tumor site. A bacterial expression system was used to produce G129R-IL2 fusion protein that maintained both G129R and IL2 activities as demonstrated by cell-based assays such as signal transducer(s) and activator(s) of transcription (STAT)5 phosphorylation, breast cancer cell proliferation, and T-cell proliferation. The antitumor activities of G129R-IL2 were demonstrated in vivo using a syngeneic model system with BALB/c mice and EMT6-hPRLR breast cancer cells. After daily injection (i.p.) of G129R-IL2 (100 microg/mouse) for 18 days, the tumor growth in the G129R-IL2-treated group was only one-third the size as compared with that of the control group. The growth rate in the G129R-IL2-treated group is also significantly slower than that of the group treated with G129R alone (200 microg/mouse/day). We hope that this novel bifunctional protein will contribute significantly to human breast cancer therapy.
Zhang
Guorong
G
Department of Microbiology and Molecular Medicine, Clemson University, Clemson, South Carolina 29634, USA.
Li
Wei
W
Holle
Lori
L
Chen
Nianyi
N
Chen
Wen Yuan
WY
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008894:Milk Proteins; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011388:Prolactin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D050799:STAT5 Transcription Factor; D013997:Time Factors; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D008894:Milk Proteins; D011993:Recombinant Fusion Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; C402398:prolactin, Arg(129)-; D011388:Prolactin