Sensitivity of newly established colorectal cell lines to cytotoxic drugs and monoclonal antibody drug conjugates

Abstract

Summary A major problem in the chemotherapy of colorectal cancers is their resistance to most cytotoxic drugs which may be due to insufficient cellular transport. Drugs conjugated to monoclonal antibodies recognising tumour antigens may overcome these difficulties by providing access of active agents to the tumour cells. The anti-tumour monoclonal antibody shown to localise in patients with colorectal cancer, 791T/36, has been investigated as a potential targeting antibody.Eight cell lines were established from surgically resected material and were shown to bind 791T/36 antibody. They were screened for their sensitivity to methotrexate, 5-fluorouracil and daunomycin. Although 5-fluorouracil is the drug of choice for chemotherapy of colorectal cancer it was the most cytotoxic drug in only 2 of the 8 cell lines. Only the 4 cell lines which were resistant to methotrexate showed less cytotoxicity with methotrexate than 5-fluorouracil. The cell lines which were resistant to methotrexate were more sensitive to 791T/36-methotrexate conjugates. Daunomycin was the most cytotoxic drug in 4 of the 8 cell lines. However, a similar cytotoxicity was observed for free drug and 791T/36 daunomycin in the two lines tested.Selective monoclonal antibody drug conjugates may offer a solution to treatment of tumours which are resistant to classical chemotherapeutic agents. This is the first report to show that newly established cell lines that are resistant to classical chemotherapeutic agents are rendered sensitive when the drug enters the cell as a drug monoclonal antibody carrier.

Effects of methotrexate-carcinoembryonic-antigen-antibody immunoconjugates on GW-39 human tumors in nude mice

“…Apparently, then, increasing the targeting of MTX to colorectal carcinoma cells can improve its cytotoxic action. This is consistent with the findings of Durrant et al [5] that a MTX immunoconjugate can show cytotoxic activity against MTX-resistant cells in culture.…”

“…This procedure produced an immunoconjugate with a high ratio of drug substitution and minimal loss of immunoreactivity, and demonstrated promising therapeutic effects on tumor xenografts. In addition to the tumor targeting, antibody with favored cross-membrane translocation properties has also been used as carrier to deliver cytotoxic agents into the cells to overcome the drug resistance that tends to develop in cancer chemotherapy [5].…”

Soluble Polymers as Targetable Drug Carriers

“…Preliminary data on the in vivo pharmacologic activity of DNM-anti-CEA conjugates, using CEA producing LoVo cells grafted in nude mice, confirmed the in vitro experiments (PAGE and EMOND 1983). DURRANT et al (1987) studied colorectal cancer in which many cell lines are resistant to most cytotoxic drugs. Monoclonal 791T/36 antibodies against osteogenic sarcoma cells were used.…”

Amino Acid Sequence Analysis, Gene Construction, Cloning, and Expression of Gelonin, a Toxin Derived fromGelonium multiflorum

“…The samples were briefly centrifuged (12,500 x g) and loaded on 15% SDS-PAGE gels (Bio-Rad Mini Protean II). The samples were electrophoresed for 75 minutes at 150 V at room temperature.…”