Relationships between the structure of taxol analogs and their antimitotic activity

Guéritte-Voegelein, Françoise; Guénard, Daniel; Lavelle, François; Goff, M T Le; Mangatal, L.; Potìer, Pierre

doi:10.1021/jm00107a017

Cited by 526 publications

(199 citation statements)

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“…It acts by enhancing microtubule assembly and inhibiting tubulin depolymerization, thus disrupting cell division (Schiff et al, 1979;Guéritte-Voegelein et al, 1991;Rowinsky and Donehower, 1995). This mechanism of action is unlike any of the standard cytotoxic agents, and therefore docetaxel has the potential for activity against human solid tumours, including PC, that are refractory to established anti-cancer agents.…”

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confidence: 99%

Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study

et al. 1999

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Pancreatic ductal cancer (PC) is difficult to treat, with most patients surgically unresectable at the time of diagnosis. Moreover, even for those who are resected, the risk of recurrence is exceedingly high, and the outcome remains unsatisfactory. The prognosis of unresectable PC patients is also extremely poor, mainly because currently available chemotherapeutic agents are largely ineffective. Accordingly, there is a clear need for new, effective agents in the management of PC. New agents with unique mechanisms of action are attractive candidates for clinical trials with the hope that their anti-tumour activity will be translated into long-term survival.Docetaxel, which is a member of the family of taxanes, is one of the most important new chemotherapeutic agents to be found in recent years (Bissett et al, 1993;Cortes and Pazdur, 1995;Eisenhauer, 1995). It acts by enhancing microtubule assembly and inhibiting tubulin depolymerization, thus disrupting cell division (Schiff et al, 1979;Guéritte-Voegelein et al, 1991;Rowinsky and Donehower, 1995). This mechanism of action is unlike any of the standard cytotoxic agents, and therefore docetaxel has the potential for activity against human solid tumours, including PC, that are refractory to established anti-cancer agents. In fact, two phase II trials of advanced PC, which were conducted in France and the USA, have reported high response rates (20%) and relatively longer survival with the drug administered at 100 mg m Ϫ2 over a 1-h period (Rougie et al, 1994;Abbruzzese et al, 1995).We report here our results of a cooperative phase II study of moderate-dose (60 mg m -2 ) docetaxel in Japanese patients with previously untreated metastatic PC. In our country, the recommended dose for phase II trials of docetaxel is 60 mg m Ϫ2 infused over a 1-h session, because a Japanese phase I trial determined the maximum-tolerated dose (MTD) to be 70-90 mg m Ϫ2 , with leucocytopenia as the dose-limiting toxicity (Taguchi et al., 1994). PATIENTS AND METHODS PatientsPatients eligible for study entry had metastatic PC for which they had not received any treatment. Each patient was required to meet the following eligibility criteria: a performance status (PS) of 0-2; 15-74 years of age; at least one bidimensionally measurable tumour; estimated life expectancy ≥ 2 months after study entry; adequate renal function (normal serum creatinine and blood urea nitrogen levels); adequate liver function (total bilirubin level ≤ 1.5 mg dl Ϫ1 (or ≤ 3.0 mg dl Ϫ1 after biliary drainage if the patient had obstructive jaundice); adequate serum transaminases (GOT, GPT) levels ≤ 2 times upper normal limit (UNL) (or ≤ 3 times Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study Summary Docetaxel has been reported to show promising anti-tumour activity in pancreatic ductal cancer (PC). This study was conducted to evaluate the activity and toxicity of moderate-dose (60 mg m Ϫ2 ) docetaxel in Japanese chemo-naive patients with measurable metastatic PC. The pa...

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Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study

et al. 1999

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“…In the case of OXL treatment group, they have a specific gene expression profiles. The gene expression changes of stress activated protein kinase alpha II [22] and opioid receptor sigma 1 [15] were related with P-glycoprotein activity. And OXL has included the P-glycoprotein inhibitor.…”

Section: Discussionmentioning

confidence: 99%

“…Paclitaxel (PCT, Taxol) have a specific action mechanism of inhibition of microtubule disassembly affecting cell division [15]. PCT inhibited various experimental tumors [35].…”

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cDNA Microarray Gene Expression Analysis and Toxicological Phenotype for Anticancer Drug

Lee

Lee²,

Jeon³

et al. 2004

The Journal of Veterinary Medical Science

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ABSTRACT. Toxicogenomics, the subdiscipline that merges genomics with toxicology, hold the promise to contributing toward the goal of elucidating mechanism by studying genomic profiling related with various drugs. The application of gene expression profiling technology to examine multiple genes and signaling pathways promises a significant advance in understanding the toxic mechanisms of var ious drugs and prediction of new drug candidate. Toxicogenomics is emerging field combining genomics and bioinformatics to identify and characterize mechanisms of toxicity of drug and various compounds. The principal hypothesis underlying on this field is that ch emicalspecific pattern of altered gene expression is related with each chemicals properties, especially toxicological property, and it will be revealed using high-density microarray analysis of sample from exposed organisms. So, in this study we compare the gene expression pattern of two anticancer drugs paclitaxel and orally absorbable paclitaxel, using the cDNA microarray. And from the result of this study, it is possible to provide the new possibility for genome-wide insight into mechanism of their anticancer activity and toxicological phenotype. KEY WORDS: anti-cancer agent, cDNA microarray, orally absorbable paclitaxol, paclitaxel, toxicogenomics.

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“…Intracellular redistribution of the drug should also be considered since such a mechanism has been described in several resistant cell lines (Hindenburg, 1987;Cole, 1992). However, this mechanism could induce resistance to several functionally unrelated drugs while J82-NVB cell resistance is limited to vinca alkaloids and taxoids which share a common target site: tubulin (Gueritte-Voegelein et al, 1991;Jordan et al, 1991). Therefore, J82-NVB cell resistance is most probably linked to the alteration of some microtubule property.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of a navelbine-resistant bladder carcinoma cell line cross-resistant to taxoids

Debal¹,

Allam²,

Morjani³

et al. 1994

Br J Cancer

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Summary A bladder carcinoma cell line (J82) was selected for resistance to the new vinca alkaloid navelbine. The resistance factor of the resistant subline (J82-NVB) to navelbine was 17. P-glycoprotein was not detected in the membrane of J82-NVB cells. The lack of cross-resistance to multidrug-resistant (MDR) drugs such as doxorubicin, epipodophyllotoxins and colchicine, the absence of increase in navelbine efflux and the fact that a reduced accumulation of the drug cannot account for the resistance level confirmed that the phenotype of resistance of J82-NVB cells is not a classical MDR phenotype. Moreover, verapamil did not reverse the resistance of J82-NVB cells. The cells were cross-resistant to vinca alkaloids and taxoids which share the same target protein: tubulin. Analysis of microtubules using immunofluorescence showed that disassembly of the microtubular network occurred for the same concentration of navelbine in sensitive and resistant cells. However, after treatment with a concentration of navelbine inducing depolymerisation in both sensitive and resistant cells, reassembly of the microtubular network was observed only in resistant cells. This study suggests that the mechanism of resistance of J82-NVB cells involves recovery from the inhibition of microtubule dynamics induced by drug treatment.The vinca alkaloids are a group of antimitotic drugs widely used in cancer chemotherapy. Their antineoplastic activity is related to their ability to alter microtubule dynamics (Binet et al., 1989;Jordan et al., 1991) causing the arrest of the cells at metaphase. However, the therapeutic efficacy of vinca alkaloids, as well as that of other anti-tumour drugs, may be reduced by the emergence of tumour cell resistance. One of the major mechanisms of resistance to vinca alkaloids, called multidrug resistance (MDR), is manifested by crossresistance to several structurally and functionally unrelated compounds such as vinca alkaloids, anthracyclines, epipodophyllotoxins, taxol, colchicine, actinomycin D and some other drugs (Beck, 1987;Pastan & Gottesman, 1987;Endicott & Ling, 1989). Classic MDR is characterised by the overexpression of a membrane glycoprotein (P-glycoprotein) which functions as a drug transporter, leading to a decreased cellular accumulation of cytostatics (Kartner et al., 1983). Several rnembrane transporters different from P-glycoprotein have also been described (McClean & Hill, 1992). Other types of resistance to vinca alkaloids have been reported, involving decreased uptake of the drug (Haber et al., 1989) or alterations of the target protein: tubulin (Houghton et al., 1985;Tsuruo et al., 1986a; Pain et al., 1988;Cabral & Barlow, 1989;Ohta et al., 1993).In order to study the mechanisms of resistance to the new vinca alkaloid navelbine (NVB) (Potier, 1989), two resistant sublines (J82-NVB and K562-NVB), respectively derived from the bladder carcinoma J82 cell line and the leukaemia K562 cell line, were selected by exposure to navelbine. Although the K562-NVB subline appeared to be a classic MDR c...

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Relationships between the structure of taxol analogs and their antimitotic activity

Cited by 526 publications

References 1 publication

Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study

Phase II study of docetaxel in patients with metastatic pancreatic cancer: a Japanese cooperative study

cDNA Microarray Gene Expression Analysis and Toxicological Phenotype for Anticancer Drug

Characterisation of a navelbine-resistant bladder carcinoma cell line cross-resistant to taxoids

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