Epidermal growth factor receptors in human breast carcinoma cells: a potential selective target for transforming growth factor alpha-Pseudomonas exotoxin 40 fusion protein.
Epidermal growth factor (EGF) receptors are expressed in high levels by some poor prognosis breast tumors. We have examined the cytotoxic effect of the tumor growth factor alpha (TGF alpha)-delta Cys-Pseudomonas exotoxin (PE40) recombinant fusion protein on normal and tumorigenic human breast epithelial cells in vitro and in vivo. The MDA-468, MDA-231, BT-20, and MCF-7ADR estrogen receptor-negative, EGF receptor-rich breast cancer lines were exquisitely sensitive in vitro to TGF alpha-delta Cys-PE40 with a 50% inhibitory concentration of < or = 0.02 nM. The estrogen receptor-positive, low EGF receptor MCF-7, ZR75-1, and T47D cells were less sensitive to the fusion toxin with a 50% inhibitory concentration of > 0.2 nM. The nontumorigenic cell lines 184, 184A1, and 184B5 were relatively resistant to TGF alpha-delta Cys-PE40 despite exhibiting high levels of EGF receptors. Continuous i.p. administration of TGF alpha-delta Cys-PE40 via an osmotic minipump at a dose of 0.4 microgram/g/day over 7 days inhibited MDA-468, MA-231, and BT-20 but not MCF-7 tumor growth in female athymic mice. Host tissue toxicity was not observed with this dose of TGF alpha-delta Cys-PE40. Mixed MDA-468/MCF-7 tumors were established in nude mice after coinoculation of both cell types in estrogen-supplemented animals. EGF receptor immunohistochemistry and immunoblot procedures indicated that TGF alpha-PE40 eliminated the MDA-468 cells while sparing the adjacent MCF-7 cells. By immunoblot, EGF receptors were consistently more abundant in tumor tissue than in adjacent nontumor tissue from the same mastectomy specimen (n = 7). These data support the notion that EGF receptors can be selectively targeted in human breast cancer cells for the delivery of antitumor agents. Further clinical studies with TGF alpha-delta Cys-PE40 and other chimeric toxins using the same cellular target will address this possibility.
Arteaga
C L
CL
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232.
Hurd
S D
SD
Dugger
T C
TC
Winnier
A R
AR
Robertson
J B
JB
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005098:Exotoxins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016211:Transforming Growth Factor alpha / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005098:Exotoxins; D016211:Transforming Growth Factor alpha; C083452:transforming growth factor alpha-Pseudomonas exotoxin A (40); D004815:Epidermal Growth Factor; D066246:ErbB Receptors