tezacitabine and Colorectal-Neoplasms

Physicians and patients alike have been heartened by the recent advances in the treatment of colorectal cancer. The emergence of novel agents that are active in the treatment of this devastating disease, such as cetuximab and bevacizumab, has been particularly notable. However, even before these recent events, a substantial change in prognosis for patients with metastatic colorectal cancer had occurred as a result of advances in traditional chemotherapeutic agents. Refinements in dose, schedule, and sequence continue to be made that could lead to further improvements in outcomes. Additionally, new chemotherapeutic agents with promise for activity in colorectal cancer are being studied. Chemotherapy is likely to remain a central element of the treatment strategy. Our understanding of its current role is discussed in this article.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Clinical Trials as Topic; Colorectal Neoplasms; Deoxycytidine; Epothilones; Fluorouracil; Glutamates; Guanine; Humans; Indoles; Organoplatinum Compounds; Oxaliplatin; Pemetrexed

(E)-2'-deoxy-2'-(fluoromethylene)-cytidine (FMdC), a deoxycytidine analog displaying a very high toxicity toward a variety of solid tumor cell lines and xenografts, is activated intracellularly by deoxycytidine kinase (dCK). We have compared cytotoxicity of FMdC towards a human promyeolocytic leukemia line HL-60 and a human colorectal carcinoma line COLO-205. Despite dCK activity being by far the highest in cells of lymphoid origin, the effects of FMdC were detectable at the lowest drug concentration only in a solid tumor cell line, and at higher concentrations they were qualitatively similar in the two tumor lines (increased cell protein content, cell cycle block and apoptosis). Apparently, low dCK activity in solid tumor cells sufficiently activates FMdC to yield cytotoxic effects, while high dCK activity in leukemia cells does not increase its cytotoxicity.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Deoxycytidine; Drug Screening Assays, Antitumor; HL-60 Cells; Humans; Leukemia, Promyelocytic, Acute; Tumor Cells, Cultured