Synergism of Cytotoxic Effects of Vinorelbine and Paclitaxel in Vitro

Budman, Daniel R.; Calabro, Anthony; Wang, Long G.; Liu, Xiao M.; Stiel, Lily; Adams, Laurel M.; Kreis, Willi

doi:10.3109/07357900009012201

Cited by 37 publications

(21 citation statements)

References 26 publications

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“…Synergy occurred when vinorelbine was applied before paclitaxel, or when the drugs were applied concurrently and left for 96 h (8). Antagonism was observed when the order was reversed (80) or with alternating applications starting with either agent (81). The opposite was observed in studies of human lung cancer lines, where synergy was observed with alternating application (82).…”

Section: Discussionmentioning

confidence: 86%

Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies

Uppal

Li²,

Wendt³

et al. 2007

Int J Oncol

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Abstract. Subcellular distribution of mass can be analyzed by a technique that involves culturing cells on interferometers and digitizing their interference contours. Contour sampling resulted in 102 variables per cell, which were predictors of oncogenic transformation. Cell phenotypes can be deconstructed by use of latent factors, which represent the covariance of the real variables. The reversal of the cancertype phenotype by a combination of microtubule-stabilizing and -depolymerizing agents was described previously. The implications of these results have been explored by clinicians who treated patients with the combination of docetaxel and vinorelbine (Navelbine ® ). The current study was performed to determine the effects of different combinations on phenotype and in phases of the cell cycle other than mitosis. Combinations of paclitaxel with either colchicine, podophyllotoxin, nocodazole, or vinblastine caused phenotype reversal. Paclitaxel analogue, 7-deoxytaxol, by itself caused reversal. Factors #4, (filopodia), #5 (displacement and/or deep invaginations in the periphery), #8, and #12 took on values typical of normal cells, whereas the values of #7 (p21-activated kinase), and #13 (rounding up) shifted toward the cancer-type. All combinations altered microtubule arrangement at the cell edge. Delivery schedules and drug ratios used in clinical studies were subjected to analysis. Clinical response rates were better when the combination was not interspersed with a single agent (P=0.004). The results support the idea that efficacy depends upon simultaneous exposure to both agents, and suggest a novel mechanism for combination therapies. These therapies appear to restore in transformed cells some of the features of a contactinhibited cell, and to impede progress through the cell cycle even when provided at nanomolar concentrations.

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Section: Discussionmentioning

confidence: 86%

Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies

Uppal

Li²,

Wendt³

et al. 2007

Int J Oncol

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“…In contrast to paclitaxel, vinorelbine binds microtubules and prevents their polymerisation, thus interfering with mitosis (Krikorian and Breillout, 1991). Previous studies have demonstrated that independent of the type of effect by the antimicrotubule agent on microtubule assembly (polymerisation or depolymerisation), these drugs exhibit the ability to promote apoptosis in cancer cells (Wang et al, 1999bBudman et al, 2000;Charles et al, 2001;Fan et al, 2001;Liu et al, 2001). One of mechanisms of vinorelbine-induced apoptosis is thought to be the upregulation of p21 and p53.…”

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confidence: 99%

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

et al. 2003

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To study the mechanisms of the development of hormone refractory prostate cancer, we established an androgen-independent (AI) prostate cancer cell line derived from hormone-dependent (AD) LNCaP cells. Our previous studies have demonstrated that AI cells are deficient in expression of p21 WAFl/CIP1 (p21) due to overexpressed AR and are resistant to apoptosis. In this study, the induction of p53 and p21 expression by vinorelbine (Navelbine) was compared between AD and AI cells in an attempt to understand the difference(s) in apoptotic signalling pathways in these cells. Using a series of deletion of p21 reporter constructs, we found that vinorelbine mediated p21 induction in a p53-dependent manner in AD cells. In contrast, p21 expression restored by vinorelbine in AI cells was found to be through both p53-dependent and-independent pathways. In the absence of two p53 binding sites, Spl-3 and Spl-4 sites, in the promoter of human p21 gene, were found to be required for vinorelbine-mediated p21 activation. No p21 induction was observed by paclitaxel in AI cells. Exposure of AI cells to paciltaxel followed by vinorelbine produced synergism. Our data, thus, provide a basis for the synergistic combination of vinorelbine and paclitaxel for the treatment of advanced prostate cancer.

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“…The rationale for administering vinorelbine in association with paclitaxel in anthracycline-pretreated breast cancer patients centres mainly on the documented activity of the two drugs in anthracycline refractory patients (Crown et al, 2002) and on the synergism of the cytotoxic effects of the two drugs in preclinical models (Photiou et al, 1997;Budman et al, 2000). The addition of infusional 5-FU might further increase the activity of this combination.…”

Section: Discussionmentioning

confidence: 99%

“…All drugs were administered on an outpatient basis. Since preclinical data suggested that the sequence of administration of paclitaxel and vinorelbine was predictive for treatment efficacy (Photiou et al, 1997;Budman et al, 2000), vinorelbine infusion preceded paclitaxel infusion. Dose modifications were performed as follows: in case of myelosuppression, if the WBC count was p2500 ml À1 and/or the platelet count was less than 100 000 ml À1 , then 5-FU was continued but both paclitaxel and vinorelbine at that day were omitted.…”

Section: Treatment Schedulementioning

confidence: 99%

“…The combination of vinorelbine and paclitaxel is thought to create a total microtubule poison that offers theoretical advantages deriving from the potential synergy between the two drugs when given together. Preclinical data have shown that paclitaxel and vinorelbine were synergistic in vitro (Photiou et al, 1997;Budman et al, 2000), while in vivo their combination produced a significantly greater proportion of cell kill of transplanted p388 murine leukaemia cells than either agent alone (Knick et al, 1995). The combination of paclitaxel and vinorelbine has been evaluated in a number of phase I and II trials.…”

mentioning

confidence: 99%

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Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

Berruti¹,

Bitossi²,

Gorzegno³

et al. 2005

Br J Cancer

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We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m À2 on days 1 and 15, PTX 60 mg m À2 on days 1, 8 and 15 and continuous infusion of 5-FU at 200 mg m À2 every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable.

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Synergism of Cytotoxic Effects of Vinorelbine and Paclitaxel in Vitro

Cited by 37 publications

References 26 publications

Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies

Pattern analysis of microtubule-polymerizing and -depolymerizing agent combinations as cancer chemotherapies

Unique induction of p21WAF1/CIP1expression by vinorelbine in androgen-independent prostate cancer cells

Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines

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