Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers

Abstract

Previous studies have demonstrated a synergistic interaction between rhuMAb HER2 and the cytotoxic drug cisplatin in human breast and ovarian cancer cells. To de®ne the nature of the interaction between rhuMAb HER2 and other classes of cytotoxic drugs, we applied multiple drug eect/combination index (CI) isobologram analysis to a variety of chemotherapeutic drug/rhuMAb HER2 combinations in vitro. Synergistic interactions at clinically relevant drug concentrations were observed for rhuMAb HER2 in combination with cisplatin (CI=0.48, P=0.003), thiotepa (CI=0.67, P=0.0008), and etoposide (CI=0.54, P=0.0003). Additive cytotoxic eects were observed with rhuMAb HER2 plus doxorubicin (CI=1.16, P=0.13), paclitaxel (CI=0.91, P=0.21), methotrexate (CI=1.15, P=0.28), and vinblastine (CI=1.09, P=0.26). One drug, 5-¯uorouracil, was found to be antagonistic with rhuMAb HER2 in vitro (CI=2.87, P=0.0001). In vivo drug/rhuMAb HER2 studies were conducted with HER-2/neu-transfected, MCF7 human breast cancer xenografts in athymic mice. Combinations of rhuMAb HER2 plus cyclophosphamide, doxorubicin, paclitaxel, methotrexate, etoposide, and vinblastine in vivo resulted in a signi®cant reduction in xenograft volume compared to chemotherapy alone (P50.05). Xenografts treated with rhuMAb HER2 plus 5-¯uorouracil were not signi®cantly dierent from 5-uorouracil alone controls consistent with the subadditive eects observed with this combination in vitro. The synergistic interaction of rhuMAb HER2 with alkylating agents, platinum analogs and topoisomerase II inhibitors, as well as the additive interaction with taxanes, anthracyclines and some antimetabolites in HER-2/neuoverexpressing breast cancer cells demonstrates that these are rational combinations to test in human clinical trials.

Recombinant humanised anti-HER2/neu antibody (Herceptin®) induces cellular death of glioblastomas

“…This result suggests a correlation between the HER2/neu receptors density and the effect of ADCC. Similar correlation was reported for gastric adenocarcinomas (Pegram et al, 1999). Microglia was found to make up 7.5 -9% of the total glial population in white matter (Akiyama and Mc Geer, 1990).…”

“…The effect of Herceptin s was first demonstrated for breast cancer (Pegram et al, 1999), then apoptotic effects were reported in different cancers (Büchler et al, 2001;Fujimura et al, 2002;Kono et al, 2002). We report similar results with GBM cell lines: Herceptin s induces a significant apoptosis induction at 24 h. Most studies reported significant results after 72 h except one on ovarian adenocarcinoma, which was significant after 24 h (Fujimura et al, 2002).…”

“…This difference could explain the greater importance of HER2/neu activity on GBM physiology and the greater effect of its blockage. Moreover, the effect of Herceptin s could be increased by synergistic effects with several chemotherapies (as etoposide or cisplatin; Pegram et al, 1999).…”

C‐myc gene expression alone is sufficient to confer resistance to antiestrogen in human breast cancer cells

“…24,25 In brief, 2 ϫ 10 3 cells were seeded into 96-well microplates in 200 l of complete medium. After overnight attachment, various additions (e.g., ICI, ICIϩdox, ICIϩ17␤-estradiol) were made.…”

Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial

“…The rationale for the combination of cytotoxic agents with trastuzumab is based on the highly synergistic effects of these two treatment strategies observed in many in vitro studies suggesting also a high potential for an existing clinical benefit [7][8][9]. Slamon et al described in their landmark paper the highly significant reduction in the risk of beast cancer death by 20% due to the combination therapy of trastuzumab plus anthracycline/cyclophosphamide chemotherapy.…”