Reduced in vivo lung metastasis of a breast cancer cell line after treatment with Herceptin mAb conjugated to chemotherapeutic drugs.
Anthracyclines and taxanes have remarkable anticancer efficacy, but have poor selectivity and high toxicity. Targeted delivery of chemotherapeutics has emerged as a strategy to achieve higher drug levels at the tumor site, to spare noncancerous tissue and potentially to use lower systemic drug doses, thus preventing side effects. In this study, we targeted the HER2 receptor using the monoclonal antibody (mAb) Herceptin (Trastuzumab) chemically conjugated to Doxorubicin or Taxol. In vitro, drug-Herceptin conjugates exhibited cytotoxicity comparable to equimolar concentrations of free drugs, with the benefit that the cytotoxicity of the conjugates was selective for cells expressing the HER2 target. In vivo, treatment of tumor-bearing mice with Taxol-Herceptin conjugates had a reduction of primary tumors comparable to equivalent doses of free drugs. However, Taxol-Herceptin conjugates significantly reduced metastasis compared with equivalent doses of free drugs. Thus, the data support the concept that conjugates might target metastasis better than primary tumors. This would offer a potential therapeutic approach for management of metastatic breast cancer.
Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
A Galan
AG
Garcia
H
H
Nedev
K
K
Bijian
J
J
Su
M A
MA
Alaoui-Jamali
H U
HU
Saragovi
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004317:Doxorubicin; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human