General and Recent Aspects of the Chemistry and Structure Activity Relationships of Taxoids

Guéritte, Françoise

doi:10.2174/1381612013397429

Cited by 79 publications

(33 citation statements)

References 56 publications

(93 reference statements)

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“…The results of the preventive study gave first evidence of the dual action of sagopilone on osteoclasts and tumor cells. Thus, the compound was tested in the more aggressive therapeutic setting compared with paclitaxel, which was approved for the treatment of metastatic breast cancer in 1994 (21).…”

Section: Discussionmentioning

confidence: 99%

Sagopilone Inhibits Breast Cancer Bone Metastasis and Bone Destruction Due to Simultaneous Inhibition of Both Tumor Growth and Bone Resorption

Strube

Hoffmann²,

Stepina³

et al. 2009

Clinical Cancer Research

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Purpose: Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a "vicious cycle" of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo, and here we report its activity in the MDA-MB-231(SA) breast cancer bone metastasis mouse model. Experimental Design: The potency of sagopilone was determined in treatment models simulating the adjuvant (preventive) and metastatic (therapeutic) settings in the clinic. Results: We showed that sagopilone inhibited tumor burden and bone destruction, in addition to reducing tumor-induced cachexia and paraplegia. The reduction in osteolytic lesions, tumor growth in bone, and weight loss was statistically significant in the preventive model compared with the vehicle group. In the therapeutic model, sagopilone treatment significantly lowered the number of activated osteoclasts and significantly reduced the osteolytic lesion area, bone volume loss, and bone resorption compared with vehicle treatment while simultaneously inhibiting tumor burden. An in vitro assay confirmed that sagopilone inhibited osteoclast activation without cytotoxic effects, whereas paclitaxel resulted in lower inhibition and high levels of cytotoxicity. Conclusions: Sagopilone seems to inhibit the vicious cycle at both the tumor growth and bone resorption stages, suggesting the possibility for substantial benefit in the treatment of patients with breast cancer at risk from bone metastases or with bone lesions already present. Phase II clinical trials with sagopilone in patients with breast cancer are ongoing.Bone is the most common site for a distant metastasis in women with breast cancer (1), with a reported incidence of up to 75% (2, 3) and an average survival time of ∼2 years after diagnosis (3). Symptoms of bone metastases include skeletal complications and bone pain, which affects up to 80% of patients and greatly impacts on their quality of life (4).Primary breast tumors express osteolytic and osteoblastic factors, stimulating different types of bone metastases, with osteolytic lesions occurring more commonly (5, 6). The development of osteolytic bone metastases has been described as a vicious cycle, with increased osteoclast activity implicated as the predominant mechanism of bone destruction (6). Tumor cells produce factors, such as parathyroid hormone-related protein, which are responsible for an increase of osteoclast activity and consequent bone resorption. Growth factors stored in bone and released during bone resorption in turn stimulate tumor cell growth, thus perpetuating the vicious cycle. The quality of life of breast cancer patients could be considerably increased by a potent inhibitor of bone metastasis (7), and a drug that could simultaneously and effectively inhibit both tumor cell growth and osteoclast activity would have great potential...

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Section: Discussionmentioning

confidence: 99%

Sagopilone Inhibits Breast Cancer Bone Metastasis and Bone Destruction Due to Simultaneous Inhibition of Both Tumor Growth and Bone Resorption

Strube

Hoffmann²,

Stepina³

et al. 2009

Clinical Cancer Research

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“…The first group of these compounds to be studied in detail was paclitaxel and structurally related taxoids (Schiff et al, 1979;Guéritte, 2001), and interest in the taxoids became more intense as it became clear that they had good activity against human neoplasms (Cortes and Pazdur, 1995;Rowinsky and Donehower, 1995). A number of more recently described drugs with a taxoid-like mechanism of action seem to bind in the same or, perhaps, an overlapping site on tubulin polymers as paclitaxel, based on their acting as competitive inhibitors of the binding of paclitaxel to tubulin (Bollag et al, 1995;Kowalski et al, 1997a,b;Long et al, 1998;Hamel et al, 1999).…”

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confidence: 99%

Laulimalide and Paclitaxel: A Comparison of Their Effects on Tubulin Assembly and Their Synergistic Action When Present Simultaneously

Gapud¹,

Bai²,

Ghosh³

et al. 2004

Mol Pharmacol

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Previous work has shown that laulimalide, a sponge-derived natural product, resembles paclitaxel in enhancing tubulin assembly and in its effects on cellular microtubules. The two compounds, however, seem to have distinct binding sites on tubulin polymer. Nearly equimolar amounts of tubulin, laulimalide, and paclitaxel are recovered from microtubules formed with both drugs. In the present study, we searched for differences between laulimalide and paclitaxel in their interactions with tubulin polymer. Laulimalide was compared with paclitaxel and epothilone A, a natural product that competes with paclitaxel in binding to microtubules, for assembly properties at different temperatures and for effects of GTP and microtubule-associated proteins on assembly. Although minor differences were observed among the three drugs, their overall effects were highly similar, except that aberrant assembly products were observed more frequently with paclitaxel and that the polymers formed with laulimalide and epothilone A were more stable at 0°C. The most dramatic difference observed between laulimalide and epothilone A was that only laulimalide was able to enhance assembly synergistically with paclitaxel, as would be predicted if the two drugs bound at different sites in polymer. Because stoichiometric amounts of laulimalide and paclitaxel can cause extensive tubulin assembly, maximum synergy was observed at lower temperatures under reaction conditions in which each drug alone is relatively inactive. Laulimalide-induced assembly, like paclitaxel-induced assembly, was inhibited by drugs that inhibit tubulin assembly by binding at either the colchicine-or vinblastine-binding site. When radiolabeled GTP is present in a reaction mixture with either laulimalide or paclitaxel, nucleotide hydrolysis occurs with incorporation of radiolabeled GDP into polymer.

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“…The taxanes, Taxol (paclitaxel) and Taxotere (docetaxel), increase MT stability along the entire length of MTs [1]. Taxanes are widely used to halt breast tumors, because they block mitosis and metastasis, and promote apoptosis, though some breast cancers are unpredictably refractory to taxanes, even at levels high enough that toxic side-effects ensue [2]. We set out to test for MTstabilizing drugs that act in all cell types and are mechanistically distinct from taxanes, as potentially promising new therapies.…”

Section: Security Classificationmentioning

confidence: 99%

Novel Microtubule-Stabilizing Reagents

Bulinski¹

2005

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General and Recent Aspects of the Chemistry and Structure Activity Relationships of Taxoids

Cited by 79 publications

References 56 publications

Sagopilone Inhibits Breast Cancer Bone Metastasis and Bone Destruction Due to Simultaneous Inhibition of Both Tumor Growth and Bone Resorption

Sagopilone Inhibits Breast Cancer Bone Metastasis and Bone Destruction Due to Simultaneous Inhibition of Both Tumor Growth and Bone Resorption

Laulimalide and Paclitaxel: A Comparison of Their Effects on Tubulin Assembly and Their Synergistic Action When Present Simultaneously

Novel Microtubule-Stabilizing Reagents

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