Peloruside A and laulimalide are potent microtubule-stabilizing natural products with a mechanism of action similar to that of paclitaxel. However, the binding site of peloruside A and laulimalide on tubulin remains poorly understood. Drug resistance in anticancer treatment is a serious problem. We developed peloruside Aand laulimalide-resistant cell lines by selecting 1A9 human ovarian carcino...

Majority of ovarian cancer patients have advanced disease (stage III or IV) at diagnosis and the prognosis of these patients is poor in spite of aggressive surgery. Therefore chemotherapy has gained a fundamental role in the therapeutic approach of ovarian cancer. Platinum compounds in combination with alkylating agents and taxoids have the higher antitumor activity in ovarian cancer, while the...

A newly synthesized taxoid originally from the Japanese yew Taxus cuspidata, 5-O-benzoylated taxinine K (BTK) was examined for its ability to reverse P-glycoprotein (P-gp) and multidrug resistance protein (MRP)-mediated multidrug resistance. BTK reversed the resistance to paclitaxel, doxorubicin (ADM), and vincristine (VCR) of KB-8-5 and KB-C2 cells that overexpress P-gp by directly interacting...

Increased abundance of βII- and βIII-tubulin isotypes in cancer cells confers resistance to vinca and taxoid site drugs; however, the role of these isotypes in the acquired resistance of cancer cells to non-vinca or non-taxoid site binding agents has not been described. Peloruside A (PLA) and laulimalide are the only known non-taxoid site microtubule-stabilizing agents. A human ovarian cancer c...

Docetaxel (Taxotere) is a semisynthetic taxoid that possesses significant activity as a single agent in the treatment of patients with non-small-cell lung cancer. In previously untreated patients with non-small-cell lung cancer, 100 mg/m2 of docetaxel administered as an intravenous infusion over 1 hour once every 3 weeks produced response rates that ranged from 21% to 38% and median survivals o...

Aberrant epigenetic regulation, such as CpG island methylation and associated transcriptional silencing of genes, has been implicated in a variety of human diseases, including cancer. Methylation of genes involved in apoptosis, including the DNA mismatch repair (MMR) gene hMLH1, can occur in tumor models of resistance to chemotherapeutic drugs. However, the relevance for acquired resistance to ...

The early steps in the biosynthesis of Taxol involve the cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene followed by cytochrome P450-mediated hydroxylation at C5, acetylation of this intermediate, and a second cytochrome P450-dependent hydroxylation at C10 to yield taxadien-5 alpha-acetoxy-10 beta-ol. Subsequent steps of the pathway involve additional cytochrome P450 catalyz...

Increased abundance of bIIand bIII-tubulin isotypes in cancer cells confers resistance to vinca and taxoid site drugs; however, the role of these isotypes in the acquired resistance of cancer cells to non-vinca or nontaxoid site binding agents has not been described. Peloruside A (PLA) and laulimalide are the only known non-taxoid site microtubule-stabilizing agents. A human ovarian cancer cell...

Preclinical studies suggest that amifostine could protect against toxicities induced by taxoids. We conducted a clinical and pharmacokinetic pilot study to assess the feasibility and toxicity of the docetaxel plus amifostine combination and the absence of influence of amifostine on docetaxel pharmacokinetics. We included 18 previously treated women with metastatic breast cancer (median age, 58....

BACKGROUND Ovarian cancer has a poor prognosis due to advanced stage at presentation and either intrinsic or acquired resistance to classic cytotoxic drugs such as platinum and taxoids. Recent large clinical trials with different combinations and sequences of classic cytotoxic drugs indicate that further significant improvement in prognosis by this type of drugs is not to be expected. Currently...