5'-Deoxy-5-fluorouridine selective toxicity for human tumor cells compared to human bone marrow.
Studies were completed to establish the comparative cytotoxicity of 5'-deoxy-5-fluorouridine (5'-dFUrd) and other fluoropyrimidines in human bone marrow stem cells and several cultured human tumor cell lines (i.e., 47-DN and MCF-7 breast carcinomas, MG-63 osteosarcoma, HCT-8 colon tumor, Colo-357 pancreatic tumor, and HL-60 promyelocytic leukemia). In vitro clonogenic assays were used to measure cytotoxicity following a 3-hr drug exposure. 5'-dFUrd was less potent than was 5-fluorouracil or 5-fluoro-2'-deoxyuridine in all cells examined, exhibiting its best activity against the 47-DN [concentration that prevented 50% clonal growth compared to untreated control (LD50) = 32 microM] and MCF-7 (LD50 = 35 microM) breast carcinomas and MG-63 osteosarcoma (LD50 = 41 microM). Intermediate activity was observed against HCT-8 (LD50 = 200 microM) and Colo-357 (LD50 = 150 microM) gastrointestinal tumors. 5'-dFUrd had very poor activity against the HL-60 leukemia (LD50 = 470 microM). The suppression of the clonal growth of human bone marrow stem cells required the greatest amount of 5'-dFUrd (LD50 = 580 microM). With use of these studies, a therapeutic ratio (concentration that prevented 25% clonal growth compared to untreated control of bone marrow divided by LD50 of tumor) was calculated for each drug in each tumor. 5'-dFUrd had values ranging from 1.2 to 7.5 for the solid tumors and 0.5 in HL-60 cells. This was in marked contrast to 5-fluorouracil, or 5-fluoro-2'-deoxyuridine, which failed in all cases to have ratios greater than or equal to one. The results indicate that 5'-dFUrd can exhibit a cytotoxic selectivity for human tumor cells compared to human bone marrow stem cells that does not exist for 5-fluorouracil or 5-fluoro-2'-deoxyuridine. This suggests that 5'-dFUrd may be of greater therapeutic benefit in the treatment of certain human cancers than the fluoropyrimidines used currently.
D000970:Antineoplastic Agents / Q000633:toxicity*; D001853:Bone Marrow / Q000187:drug effects*; D001943:Breast Neoplasms / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D005467:Floxuridine / Q000633:toxicity*; D005472:Fluorouracil / Q000633:toxicity; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*; D012516:Osteosarcoma / Q000473:pathology
D000970:Antineoplastic Agents; D005467:Floxuridine; D005472:Fluorouracil; C025034:doxifluridine