Do β-tubulin mutations have a role in resistance to chemotherapy?

Berrieman, Helen K.; Lind, Michael; Cawkwell, Lynn

doi:10.1016/s1470-2045(04)01411-1

Cited by 130 publications

(92 citation statements)

References 30 publications

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“…The modest activity of single-agent ABT-751 in this group of patients may be due to acquired or inherent resistance mediated in part by mutations in genes encoding the h-tubulin subunits that impair binding of drugs (47,48). Therefore, we investigated whether mutations occurred in the colchicinesbinding site of h-tubulin.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

Yee

Hagey

Verstovšek

et al. 2005

Clinical Cancer Research

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Purpose: ABT-751is anoral antimitotic agent that binds to the colchicine site on h-tubulin. A phase 1study was conducted to determine the maximum tolerated dose and toxicities of ABT-751in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. Study Design: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m 2 (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m 2 (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). Results: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m 2 , with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala 185

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Section: Discussionmentioning

confidence: 99%

Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

Yee

Hagey

Verstovšek

et al. 2005

Clinical Cancer Research

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“…In mammals, there are at least six a-and seven b-tubulin isotypes, encoded by multiple genes that display differential tissue expression [Lopata and Cleveland, 1987;Ludueña, 1998]. The genes are constituted by four exons and three introns, while the nonfunctional pseudogenes lack most or all introns [Berrieman et al, 2004]. The b-tubulin isotypes are well conserved across species and have related amino acid sequences differing primarily within the C-terminal 15-20 amino acids, a region of the protein that is the putative binding site for several microtubule-associated proteins (MAPs) .…”

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confidence: 99%

Tumoral and tissue‐specific expression of the major human β‐tubulin isotypes

et al. 2010

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The beta-tubulins are microtubule components encoded by a multigene family, which produces slightly different proteins with complex expression patterns. Several widely used anticancer drugs base their activity on beta-tubulin binding, microtubule dynamics alteration, and cell division blockage. The expression of these drug targets in tumoral and normal cells could be of crucial importance for therapy outcome, unfortunately, the complex beta-tubulin expression patterns have been poorly characterized in human. In this study, we developed a quantitative RT-PCR technique that accurately determines the mRNA expression of the eight human beta-tubulin isotypes, encoding class I, IIa, IIb, III, IVa, IVb, V, and VI and applied it to 21 nontumoral tissues and 79 tumor samples belonging to seven cancer types. In the nontumoral tissues, we found that, overall, TUBB (I), TUBB2C (IVb), and TUBB6 (V) were ubiquitous, TUBB1(VI) was hematopoietic cell-specific, and TUBB2A (IIa), TUBB2B (IIb), TUBB3 (III), and TUBB4 (IVa) had high expression in brain; however, the contribution of the different isotypes to the total beta-tubulin content varied for each tissue and had a complex pattern. In tumoral tissues, most isotypes exhibited an altered expression in specific tumor types or related to tumoral characteristics. In general, TUBB3 showed a great increase in expression while TUBB6 expression was largely decreased in most tumors. Thus, normal tissues showed a complex beta-tubulin isotype distribution, which could contribute to the toxicity profile of the microtubule-binding drugs. In addition, the specific isotypes significantly altered in tumors might represent markers for drug response.

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“…One clinical study of 49 patients with nonsmall cell lung cancer suggested that paclitaxel resistance is associated with β-tubulin mutations (Monzo et al 1999). The signifi cance of this fi nding is unclear, as tubulin mutations seem to be a rare occurrence in most human tumors (Berrieman et al 2004). In addition, tubulin mutations detected in non-small cell lung cancer samples isolated from patients were determined to be due to contamination of the genomic assay by amplifi cation of pseudogenes which share homology.…”

Section: Preclinical Functional Activitymentioning

confidence: 99%

Novel microtubule-targeting agents – the epothilones

Cheng

Bradley²,

Budman

2008

BTT

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Epothilones are a new class of antimicrotubule agents currently in clinical trials. Their chemical structures are distinct from taxanes and are more amenable to synthetic modifi cation. Six epothilones have been studied in preclinical and clinical trials: patupilone (epothilone B), ixabepilone (BMS247550), BMS 310705, sagopilone (ZK-EPO), KOS-862 (epothilone D), and KOS-1584. In vitro data have shown increased potency in taxane-sensitive and taxane-resistant cancer cell lines. This enhanced cytotoxic effect has been attributed to epothilone being a poor substrate for p-glycoprotein drug resistance protein and having high affi nity to the various β tubulin isoforms. Phase I clinical data have shown different dose-limiting toxicities for each of the epothilones. These effects are drug specifi c, dose specifi c, and schedule of administration specifi c. While diarrhea and myelosuppression are the dose-limiting toxicities for patupilone and BMS 310705, respectively, neurologic toxicity, as seen with taxanes, is the dose-limiting toxicity of ixabepilone, sagopilone, and KOS-862. In an effort to decrease neurologic toxicity, investigators have modifi ed dosing schedules with limited success. Ixabepilone has the most mature clinical results with published phase II and III data, and regulatory approval for clinical use in the treatment of breast cancer. Ixabepilone has also been combined with other anticancer agents and has regulatory approval in combination with capecitabine for heavily treated breast cancer.

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Do β-tubulin mutations have a role in resistance to chemotherapy?

Cited by 130 publications

References 30 publications

Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

Tumoral and tissue‐specific expression of the major human β‐tubulin isotypes

Novel microtubule-targeting agents – the epothilones

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Do β-tubulin mutations have a role in resistance to chemotherapy?

Cited by 130 publications

References 30 publications

Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

Phase 1 Study of ABT-751, a Novel Microtubule Inhibitor, in Patients with Refractory Hematologic Malignancies

Tumoral and tissue‐specific expression of the major human β‐tubulin isotypes

Novel microtubule-targeting agents &ndash; the epothilones

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Product

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Novel microtubule-targeting agents – the epothilones