Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer.

Abstract

The efficacy and toxicity of leucovorin 500 mg/m2 administered intravenously (IV) over 30 minutes daily for five days followed in one hour by fluorouracil (5-FU) 375 mg/m2 administered IV daily for five days, each given every 3 weeks, was assessed in 54 previously treated patients with metastatic breast cancer. An overall objective response rate of 24% was achieved (95% confidence interval, 13% to 38%), with an additional 56% of patients maintaining stable disease. Eleven of 12 patients who responded had received previous 5-FU therapy. Toxicity of this regimen included grade 3 diarrhea in 13%, grade 3 or 4 mucositis in 33%, grade 3 or 4 granulocytopenia in 65%, and grade 3 or 4 thrombocytopenia in 19%. Delay of treatment was required for hematologic toxicity in 44 patients. Thirty-eight patients required dose reductions due to toxicity. Biochemical evaluation of tumor biopsy specimens obtained from 17 patients used as their own controls with and without leucovorin was performed. These studies reveal an increased stabilization of the 5-fluorodeoxyuridylate (FdUMP)-thymidylate synthase (TS) folate ternary complex with the addition of leucovorin. There was a 71% +/- 14% occupancy or inhibition of the enzyme with the use of both 5-FU and leucovorin, v 30% +/- 13% for 5-FU alone (P2 less than .037). The percent TS bound in responding patients was substantially higher than in those patients with progressive disease. Finally, the mean total tumor TS pre-therapy in seven patients was 31 fmol/mg compared with a mean of 81 fmol/mg in these same seven patients 24 hours after therapy. This 2.6-fold increase suggests that there is an induction of the enzyme, TS, with 5-FU treatment.

Escherichia coli thymidylate synthase expression protects human cells from the cytotoxic effects of 5-fluorodeoxyuridine more effectively than human thymidylate synthase overexpression

“…CH 2 FH 4 was generated by mixing FH 4 (Sigma) at a 10:1 molar ratio with formaldehyde in 100 mM KH 2 PO 4 (pH 7.2) and 50 mM ␤-mercaptoethanol as described previously. 17 …”

DNA-synthesis enzyme activity: A biological tool useful for predicting anti-metabolic drug sensitivity in breast cancer?

“…Patients with high TS levels in rectal tumour tissues before treatment showed a significant improvement in diseasefree survival from adjuvant 5-FU-based therapy (Johnston et al, 1994). Moreover, response to treatment may be associated with decreased levels of free enzyme (Swain et al, 1995). Enzyme induction in neoplastic cells when exposed to 5-FU could, on the other hand, represent an important mechanism for development of acquired resistance (Swain et al, 1995).…”

“…Moreover, response to treatment may be associated with decreased levels of free enzyme (Swain et al, 1995). Enzyme induction in neoplastic cells when exposed to 5-FU could, on the other hand, represent an important mechanism for development of acquired resistance (Swain et al, 1995).…”

“…Moreover, response to treatment may be associated with decreased levels of free enzyme (Swain et al, 1995). Enzyme induction in neoplastic cells when exposed to 5-FU could, on the other hand, represent an important mechanism for development of acquired resistance (Swain et al, 1995).Dysregulation in tumour growth arises from several factors, including cell-cycle-specific enzymes and peptide growth factors. Binding of several growth factors to their membrane receptors results in activation of an intrinsic TPK, which is a major event in these signal transduction pathways.…”

Effective treatment of advanced breast cancer with vinorelbine, 5-fluorouracil and l-leucovorin plus human granulocyte colony-stimulating factor

“…As both vinorelbine and leucovorin-modulated 5-fluorouracil (5-FU) (Lopirinzi et al 1989: Swain et al 1989: Margolin et al 1992 are known to be effective in advanced breast cancer. and because of their non-overlapping toxicity except for myelosuppression.…”