Dose-intensive vinorelbine with concurrent granulocyte colony-stimulating factor support in paclitaxel-refractory metastatic breast cancer.

Despite early diagnosis, a large proportion (up to 40%) of breast cancer patients will develop metastatic disease that is incurable with conventional treatments (Hortobagyi and Piccart-Gebhart, 1996). The choice of appropriate therapy for metastatic breast cancer is determined by several factors: pace of relapse (influenced in part by the interval between initial presentation and first relapse), hormone receptor status, previous treatment, presence or absence of visceral involvement, age and fitness (including comorbid disease), patient preference and healthcare budgets. Conventional chemotherapy regimens based on cyclophosphamide, 5-fluorouracil (5-FU) and methotrexate (CMF) or an anthracycline (FAC, FEC) achieve response rates of 40-80% in chemotherapy-naïve patients, although further relapse is the rule, usually within months of stopping treatment. Moreover, the increasing use of chemotherapy, particularly anthracycline-based regimens, in the adjuvant setting means that new treatment options are required for metastatic disease. Several agents have been developed in recent years, including the taxoids (paclitaxel and docetaxel) and vinorelbine, and these have become the second-line treatments of choice in many countries (Livingston et al, 1997;Archer et al, 1998;Carlson, 1998;Ray-Coquard et al, 1998;Valero et al, 1998).The oral fluoropyrimidine, capecitabine, has been developed as an enzymatically activated, tumour-selective agent, thereby increasing tumour concentrations of active drug and limiting exposure of normal tissue to the toxic effects of chemotherapy. Another important objective in developing capecitabine was to mimic continuous infusion 5-FU, for which response rates of 12% have been reported in heavily pretreated patients (Ng et al, 1994;Ragaz et al, 1997). This review examines oral fluoropyrimidines as an alternative or an addition to vinorelbine/taxoid therapy that offers metastatic breast cancer patients acceptable efficacy with good tolerability and ease of use. In particular, the role of capecitabine is examined as it offers the advantages of oral administration at home. NEW TREATMENT APPROACHES FOR METASTATIC BREAST CANCER TaxoidsThe taxoids are being used increasingly, either alone or in combination with other agents, in breast cancer patients whose disease has relapsed after adjuvant chemotherapy or as first-line chemotherapy for metastatic disease. Studies in patients who have received extensive previous chemotherapy have shown response rates in the range of 20-38% with paclitaxel doses of 135-300 mg/m 2 every 3 weeks, and in the range of 35-58% with docetaxel doses of 100 mg/m 2 every 3 weeks (D'Andrea and Seidman, 1997). Two prospective, randomized, phase III trials have demonstrated that docetaxel achieves superior response rates compared with either mitomycin plus vinorelbine (Nabholtz et al, 1999) or doxorubicin monotherapy (Chan et al, 1999) in anthracycline-resistant breast cancer patients. The median time to disease progression and overall survival achieved with docetaxel were si...

Section: Vinorelbinementioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Oral fluoropyrimidines among the new drugs for patients with metastatic breast cancer

Leonard

2001

“…In MBC, response rates to single doxorubicin treatment range from 52% in previously untreated patients to 28% in patients previously exposed to an alkylating agent (Esteva et al, 2001). In patients who failed to respond to anthracycline and taxanes treatment, administration of capecitabine, gemcitabine or vinorelbine has been shown to result in overall response rates of 20-25% (Livingston et al, 1997;Blum et al, 1999;Valerio et al, 2001). Gemcitabine, an antimetabolite pyrimidine analogue, and vinorelbine, which inhibits microtubule polymerisation, have been widely investigated in the treatment of MBC (Martin et al, 2007).…”

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confidence: 99%

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Alami

Paterson²,

Bélanger

et al. 2007

Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The current study was conducted to investigate further the anti-proliferative effects of xanafide in human breast cancer cell lines, in vitro and in vivo. The in vitro activity of xanafide against MCF-7, MDA-MB-231, SKBR-3 and T47D cell lines was compared to that of paclitaxel, docetaxel, gemcitabine, vinorelbine and doxorubicin. In MCF-7, xanafide demonstrated comparable total growth inhibition (TGI) concentrations to the taxanes and lower TGI values than gemcitabine, vinorelbine and doxorubicin. MCF-7 (oestrogen receptor (ER) þ /p53 wild-type) was the most sensitive cell line to xanafide. MDA-MB-231 and SKBR-3 exhibited similar sensitivity to xanafide. T47 D (ER þ /p53 mutated), showed no response to this agent. The in vivo activity of xanafide was further compared to that of docetaxel in MCF-7 and MDA-MB-231 cell lines using the hollow fibre assay. Xanafide was slightly more potent than docetaxel, at its highest dose in MCF-7 cell line, whereas docetaxel was more effective than xanafide in MDA-MB-231 cell line. Our results show that there is no relationship between sensitivity of these cell lines to xanafide and cellular levels of both isoforms of topoisomerase II and suggest that ER and p53 status and their crosstalk may predict the responsiveness or resistance of breast cancer patients to xanafide.

“…Navelbine (NVB, vinorelbine ditartrate, KW-2307) is a new vinca alkaloid analogue that has been shown to be clinically active against advanced and/or metastatic breast cancer as a single agent (Bruno et al, 1995;Gasco et al, 1997;Livingston et al, 1997). The drug has been also shown to exert objective clinical outcome in combination with other chemotherapeutic agents, such as doxorubicin, mitomycin C and ifosfamide as a first-line or second-line therapy for advanced breast cancer (Agostara et al, 1994;Spielmann et al, 1994;Hochster, 1995;Pronzato et al, 1997).…”

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Combined effect of navelbine with medroxyprogesterone acetate against human breast carcinoma MCF-7 cells in vitro

Sugiyama

Shimizu²,

Akiyama³

et al. 1998

Summary Navelbine (NVB, vinorelbine ditartrate, KW-2307), a new vinca alkaloid analogue, has been shown to be clinically effective against advanced breast cancer. In this report, the combined effect of NVB with medroxyprogesterone acetate (MPA), a synthetic progesterone derivative, was examined in vitro against human breast carcinoma MCF-7 cells. The combined effect was demonstrated to be synergistic using the isobologram and median-effect plot analyses. To elucidate the mechanism of action, we further examined effects of both drugs on cell cycle distribution of the cells in combination and/or alone. NVB at 2 nm induced apparent G1-phase accumulation as well as the induction of cyclin-dependent kinase (CDK) inhibitor p21WAF1/cIPl protein and the dephosphorylated form of retinoblastoma protein (pRb). In contrast, MPA at 0.1 gM also induced G1-phase accumulation as well as the reduced expression of cyclin Dl protein. In addition, the combination of both drugs induced augmented G1-phase accumulation, which occurred along with p21WAF1/cIPl protein induction, cyclin Dl protein reduction and pRb dephosphorylation. These results demonstrate that the synergistic combined effect of NVB with MPA was mediated through enhancement of G1-phase accumulation that resulted from the different action point(s) of each drug. Furthermore, the synergistic combined effect of NVB with MPA was also observed in other human breast carcinoma cell lines, such as T-47D and ZR-75-1. These results suggest that combination therapy of NVB with MPA in breast cancer might be effective in clinical studies.