title: Heterogeneity of chemosensitivity of colorectal adenocarcinoma determined by a modified ex vivo ATP-tumor chemosensitivity assay (ATP-TCA).
abstract: Advanced colorectal cancer (CRC) has a poor prognosis with a 5-year survival of only 5% despite treatment with chemotherapeutic agents. Response rate and overall survival varies little between the commonly used single agents, although combinations achieve better outcomes. It is well established that considerable heterogeneity exists between cancers of the same tissue type, but it has been difficult to establish this for CRC. We therefore investigated the heterogeneity of chemosensitivity in CRC using a modified version of the ex vivo ATP-tumor chemosensitivity assay (ATP-TCA) capable of handling infected tumor tissue. Fifty-three specimens of primary solid or malignant effusions of CRC were tested, of which 46 (87%) were evaluable. There were considerable differences in sensitivities between individuals. The most active single cytotoxic agents in the assay were identified as 5-fluorouracil, irinotecan and mitomycin C (MMC). Cells were exposed to combinations of drugs added simultaneously at the same concentrations tested as single agents. All drug combinations achieved greater growth inhibition than drugs used alone. MMC+gemcitabine was found to be the most effective combination in 83% of specimens. The ATP-TCA has previously been shown to be a good predictor of response to chemotherapy in other tissue types. The degree of heterogeneity demonstrated from these results suggests that the ATP-TCA could be used to identify patients who might benefit from specific chemotherapeutic agents alone or in combination.
authors.affiliation: Translational Oncology Research Centre, Queen Alexandra Hospital, Portsmouth PO6 3LY, UK.
authors.forename: Pauline A
authors.initials: PA
authors.lastname: Whitehouse
authors.forename: Louise A
authors.initials: LA
authors.lastname: Knight
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Mercer
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sharma
authors.forename: Ian A
authors.initials: IA
authors.lastname: Cree
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000255:Adenosine Triphosphate; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011786:Quality Control; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000255:Adenosine Triphosphate