Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Fluorouracil and high-dose leucovorin in previously treated patients with metastatic breast cancer. 266 35

The active metabolite of FUra, 5-fluorodeoxyuridine monophosphate (5-FdUMP), requires the presence of reduced folates to form a covalent ternary complex with the target enzyme thymidylate synthase (TS). In vitro and in vivo studies have demonstrated a potentiation of the cytotoxic effects of FUra when combined with the reduced folate, leucovorin. We have applied this concept to the treatment of metastatic breast cancer in a phase II trial, as recent clinical studies on patients with colorectal carcinoma have suggested an enhanced efficacy for the combination of FUra plus leucovorin. Patients entered on the present study are undergoing treatment with a 5-day daily regimen of leucovorin (500 mg/m2, iv) followed by FUra (375 mg/m2, iv). Toxicity and response data are currently being collected on patients who have failed "standard" combination regimens that included FUra. In patients with accessible tumor, serial biopsies are being obtained during treatment with the combination of FUra and leucovorin and during therapy with FUra alone to assess the degree of 5-FdUMP binding to the target enzyme, TS, in the presence and absence of exogenously administered leucovorin. Preliminary results from the biochemical studies suggest an enhanced saturation of TS by the fluorinated pyrimidine when administered with leucovorin.
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PMID:Preliminary results of a phase II trial for the treatment of metastatic breast cancer with 5-fluorouracil and leucovorin. 350 43

The use of leucovorin to modulate 5-fluorouracil (FUra)-mediated inhibition of thymidylate synthase has been shown both in vitro and in vivo to improve the antitumor activity of FUra. Based on the activity of this combination in previously untreated patients, we performed a study of FUra and high-dose leucovorin (HDFA) in patients with metastatic breast cancer and minimal prior chemotherapy. Patients were stratified by prior chemotherapy (or relapse within 12 months of completing adjuvant chemotherapy) versus no prior chemotherapy (or relapse at greater than 12 months since completion of adjuvant chemotherapy). FUra was given daily for 5 days at 370 mg/m2/day with HDFA, 500 mg/m2/day, beginning 24 hours before and continuing 12 hours beyond the first and last FUra doses, respectively. Two objective responses occurred among 21 patients in the pretreated group (10%; 95% confidence interval: 1-30%). Four of 36 eligible patients (11%) in the "no prior therapy group" had complete responses (95% confidence interval: 3-26%). The major toxicities were moderate leucopenia and mucositis. We conclude that FUra plus leucovorin has modest antitumor activity in metastatic breast cancer.
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PMID:Phase II trial of 5-fluorouracil and high-dose folinic acid as first- or second-line therapy for advanced breast cancer. 814 Nov 12

Pemetrexed disodium (Alimta, LY231514) is a novel, multitargeted antifolate that inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. This agent is broadly active in a wide variety of solid tumors, including breast cancer. Pemetrexed disodium has also shown clinically relevant activity in combination with gemcitabine (Gemzar). This combination is being evaluated for the treatment of metastatic breast cancer.
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PMID:Gemcitabine and Pemetrexed disodium in treating breast cancer. 1125 87

To evaluate the antitumor efficacy against metastatic breast cancer of fluoropyrimidines alone and combined with other chemotherapeutic agents, we developed a murine model of breast cancer metastatic to the lung by orthotopically implanting MDA-MB-435S breast tumors into mice. MDA tumor cells greatly metastasized to lung tissue only after the orthotopically implanted tumors were surgically removed. Measurement of the expression of enzymes involved in 5-FU metabolism showed significantly higher activity of dihydropyrimidine dehydrogenase (DPD) and lower activity of thymidylate synthase (TS) in the MDA metastases than in the orthotopically implanted tumors. Based on the enzymatic properties of metastatic tumors, the minimum toxic doses of UFT (17.5 mg/kg/day) as a DPD-inhibitory fluoropyrimidine (DIF), and of 5'-DFUR (120 mg/kg/day) as a non-DIF, were orally administered to mice with pulmonary metastasis of the breast tumor. The results showed that UFT significantly inhibited the growth of pulmonary metastases of the breast tumors, but 5'-DFUR did not. UFT seemed to inhibit the growth of the pulmonary metastases of the breast tumors in combination with paclitaxel (50 mg/kg) more than in combination with 5'-DFUR, although the antitumor efficacy of neither combination was significantly different from that of paclitaxel alone. These results suggest that combination of DIF with other chemotherapeutic drugs, such as taxanes, is required to attain high antimetastatic and antitumor efficacy against breast tumor metastases, based on the molecular characteristics of the metastatic tumors.
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PMID:[Antimetastatic and antitumor effects of fluoropyrimidines alone and combined with taxanes in a murine model of breast cancer metastatic to the lung]. 1181 85

Metastatic breast cancer is a chemotherapy-responsive disease, and significant palliation of cancer-related symptoms can be achieved with effective treatment. New treatments are needed because patients with metastatic breast cancer commonly out-live the effectiveness of currently available cytotoxic and hormonal treatments. Pemetrexed is a novel antimetabolite that inhibits three enzymes critical in purine and pyrimidine biosynthetic pathways: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Several phase II studies of pemetrexed have showed objective response rates of more than 30% in minimally pretreated metastatic breast cancer patients and approximately 20% in more heavily pretreated patients. Pemetrexed is associated with limited toxicity when administered with folic acid and vitamin B(12) supplementation and is therefore a promising agent both for palliative treatment of metastatic disease and for incorporation into combination regimens for treating newly diagnosed metastatic and early-stage breast cancer.
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PMID:Pemetrexed: a promising new treatment for breast cancer. 1202 91

Several enzymes are closely related with the mechanism of action of fluoropyrimidine (FP). Dihydropyrimidine dehydrogenase (DPD) which catalyzes 5-fluorouracil (5-FU), thymidine phosphorylase (TP), responsible for catalyzing doxifluridine to 5-FU, and thymidylate synthase (TS) were estimated for breast cancer. TP level determined by enzyme-linked immunoabsorbant assay (ELISA), DPD level by ELISA and catalytic assay and TS level by fluorodeoxyuridine monophosphate (FdUMP) binding assay were estimated for 210 specimens from 125 consenting patients with primary or metastatic breast cancer who gave consent. TS level of T1 was higher than that of T2-4 (p < 0.05). A high positive correlation was observed between TP and DPD in the same specimen. The ratio of simultaneously resected metastasis/primary and postoperative recurrent/primary never exceeded two. Enzyme level, generally decreased with or without interventing FP therapy. Enzyme level increase was frequently observed in a series of no-drug, non-FP, and FP therapy regimens. For selection of chemotherapy or estimation of chemosensitivity, TS can be used, with either TP or DPD at first surgery, and also with intervening chemotherapy after recurrence.
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PMID:[Estimation of level of enzyme induction of thymidine phosphorylase, dihydropyrimidine dehydrogenase, and thymidylate synthase in primary and recurrent breast cancer]. 1511 96

Alimta (pemetrexed) is a novel multitargeted antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed possesses antitumor activity in several solid tumors, including non-small cell lung cancer, malignant pleural mesothelioma, pancreas, colorectal, gastric, bladder, breast, and head and neck cancers. The main toxicities of the drug are myelosuppression, skin rash, and mucositis. Both myelosuppression and mucositis are more frequent in patients with high homocysteine plasma levels (an indicator of deficient vitamin B(12) and folate pools). Supplementation with vitamin B(12) and folic acid greatly reduces most severe toxicities and has been implemented in pemetrexed trials since December 1999. Pemetrexed has been tested in five phase II trials in locally advanced or metastatic breast cancer. The drug has shown an activity of around 30% in advanced breast cancer patients with minimal or no prior chemotherapy. In patients who received prior anthracyclines, response rates of 21% were reported. Responses have also been observed in a moderate proportion of patients who had been pretreated with anthracyclines, taxanes, and capecitabine. Some studies have suggested that a correlation exists between thymidylate synthase tumor expression with pemetrexed antitumor activity; this attractive hypothesis should be confirmed in further studies. The optimal dose when combined with vitamin supplementation is under current investigation in patients with breast cancer. A randomized phase II study comparing pemetrexed 600 and 900 mg/m(2) with vitamin supplementation as first-line treatment for metastatic breast cancer is ongoing.
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PMID:Clinical experience with pemetrexed in breast cancer. 1647 13

The combination of lapatinib and capecitabine is approved in Her2+ metastatic breast cancer. However, the pharmacological mechanisms for this association have not been fully elucidated. In this non-clinical study, we evaluated the efficacy of this association on a panel of six human breast cancer cell lines as a means to identify the molecular determinants of response to this combination. Cell viability was evaluated after concomitant/sequential exposure, and response/resistance determinants for each drug such as dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), thymidine phosphorylase, Bax, Bcl2, P21 levels, and phospho p42/44 and HER1/2 signaling pathway were studied. Lapatinib proved to markedly downregulate TS activity, thus suggesting a subsequent better efficacy of capecitabine. Capecitabine optimized the downregulation of p-AKT and p-P42/44 expression by lapatinib. Consequently, we observed an increase in the Bax/Bcl2 ratio and p21 protein expression in cells exposed to the combination. Overall, our data showed that whatever the schedule and the cell line were, additive to synergistic interaction was achieved in our models. The optimal in vitro combination was finally tested in tumor-bearing mice. Our results fully confirmed that associating both drugs led to a 77% reduction in tumor growth as compared with control animals in BT474-xenografted models. Taken together, this non-clinical study shows that lapatinib and capecitabine modulate each other's molecular determinants of response and that concomitant dosing seems to be the optimal way to combine these drugs. Besides, modulation of TS expression by lapatinib makes its association with capecitabine a promising way to overcome breast cancers resistant in relation with TS overexpression.
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PMID:Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants. 2162 1

Conventional preoperative chemotherapy regimens have only limited efficacy in hormone receptor positive (HR+) breast cancer and new approaches are needed. We hypothesized that capecitabine, which is effective in metastatic breast cancer, may be an active preoperative treatment for HR+ breast cancer. Women with HR+, HER2-negative operable breast cancer received capecitabine, 2000 mg/m(2) daily in divided doses for 14 days, followed by a 7-day rest period. Treatment was repeated every 21 days for a total of four cycles. The primary endpoint of the study was to determine the rate of pathological complete response (pCR). Because of slow accrual, the study was closed after 24 patients were enrolled. Three patients had a complete clinical response, and eight patients had a partial clinical response, for an overall clinical response rate of 45.8%. There were no cases of pCR. Of the 22 patients who had pathological response assessment by the Miller-Payne grading system, there were six grade 3 responses, and no grade 4 or 5 responses. Toxicity was manageable: the only grade 3 toxicities observed were one case each of diarrhea, palmar plantar erythrodysesthesia, hypokalemia, and mucositis. There was no association between baseline levels, or change in level from baseline to cycle 1, or from baseline to time of surgery, of thymidine phosphorylase (TYMP), thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), or Ki67 and pathological, clinical, or radiographic response. Preoperative capecitabine is a well-tolerated regimen, but appears not lead to pCR when used as monotherapy in HR+ breast cancer.
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PMID:A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer. 2446 80


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