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 a (TGFα)-δCys-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 TGFα-ΔCys-PE40 with a 50% inhibitory concentration of <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 TGFα-ΔCys-PE40 despite exhibiting high levels of EGF receptors. Continuous i.p. administration of TGFα-δCys-PE40 via an osmotic minipump at a dose of 0.4 ug/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 TGFα-ACys-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 TGFα-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 TGFα-ACys-PE40 and other chimeric toxins using the same cellular target will address this possibility.
|Original language||English (US)|
|Number of pages||7|
|State||Published - Sep 1994|
ASJC Scopus subject areas
- Cancer Research