The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics

Rowinsky, Eric K.; Donehower, Ross C.

doi:10.1016/0163-7258(91)90086-2

Cited by 311 publications

(170 citation statements)

References 413 publications

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“…Microtubule-targeting cancer therapies interfere with mitotic spindle dynamics and block cells in mitosis by activating the mitotic checkpoint. Therefore, microtubule poisons such as vinca alkaloids and taxanes are useful therapeutic compounds for the treatment of human cancer (Rowinsky and Donehower, 1991;Jordan et al, 1992). Tumor cells often have a defective spindle checkpoint system (Pihan et al, 2003) and attempt to progress through mitosis despite the presence of microtubule defects.…”

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confidence: 99%

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

Peng¹,

Pan²,

Liu³

et al. 2010

The Anatomical Record

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The hypoxic environment of solid tumor causes the tumor cells survive and which could protect them from death by facilitating resistance to therapy. Here, we provide evidence that hypoxia can increase tumor cell viability and proliferation through an Egr-1-dependant pathway. Hypoxia protected the microtubules from disassembly, and Egr-1 was colocalized with microtubules in different cell cycle stages. Knockdown of Egr-1 with its siRNA overcame the protection effect of hypoxia and increased the sensitivity of tumor cells to vinblastine under hypoxic conditions. Our results suggest a novel approach for increasing the sensitivity of tumor cells to chemotherapeutics that target microtubule assembly. Anat Rec, 293:414-420, 2010. V V C 2010 Wiley-Liss, Inc.

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confidence: 99%

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

Peng¹,

Pan²,

Liu³

et al. 2010

The Anatomical Record

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“…12,13 The dose-response curve for vincristine looks unusual in that at low doses the HeLa vector transfectants are more resistant than the SPF45-overexpressing cells, whereas at high doses of the drug the SPF45-overexpressing cells are more resistant that the vector control. This pattern was consistently seen in repeat experiments.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, overexpression of SPF45 is seen in numerous carcinomas including bladder, breast, colon, lung, pancreatic, and prostate carcinomas. Using HeLa cells that stably overexpress SPF45, we demonstrate that SPF45 overexpression is sufficient to confer drug resistance to doxorubicin and vincristine, two drugs from two different classes of chemotherapeutic agents 12,13 commonly used in cancer treatment. To our knowledge, this is the first study that demonstrates that overexpression of a splicing factor is sufficient to confer a multidrug-resistant phenotype to transfected cells.…”

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confidence: 99%

Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

Sampath

Long

Shepard

et al. 2003

The American Journal of Pathology

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Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance. The development of multidrug resistance is a major hurdle in the treatment of cancer. Although some genes that confer multidrug resistance are known, it is clear that many other genes remain to be identified. The characterization of novel mechanisms that lead to drug resistance would enable the development of a targeted new generation of anti-cancer drugs. To identify novel genes involved in drug resistance we performed suppressivesubtractive polymerase chain reaction analyses of the cyclophosphamide-resistant EMT6 mouse mammary tumor cells and the parental EMT6 tumors. This led to the identification of a gene that was highly homologous to a DNA damage response protein, DRT111 of Arabidopsis (unpublished observations). 1 While this work was in progress, Neubauer and colleagues, 1 identified a novel protein from the spliceosome. An analysis of all proteins present in the spliceosomal complex led to the identification of 25 previously identified proteins and 20 novel proteins. One of the novel proteins thus identified was named SPF45 (splicing factor 45 kd). This protein was identical to the one that was identified by our suppressive-subtractive polymerase chain reaction analysis. Neubauer and colleagues, 1 further showed that SPF45 was a nuclear protein that co-localizes with U1A snRNP in nuclear speckles, a known reservoir of splicing factors. [2][3][4] Recently Rappsilber and colleagues, 5 have described the identification of 311 proteins in the human spliceosomal complex of which 96 were novel proteins. Again, in this study, SPF45 was identified as a component of the spliceosome.Lallena and colleagues, 6 demonstrated that SPF45 regulates the alternate splicing of the Drosophila sexlethal gene (sxl). SXL protein is expressed only in female flies, but not in males. 7 Exon3 of Sxl plays a very important role in determining the expression of SXL because its inclus...

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“…Docetaxel is an antimicrotubule agent that enhances polymerisation of tubulin into stable microtubules and inhibits microtubule depolymerisation. This leads to a disruption of the equilibrium within the microtubule system and ultimately leads to cell death (Rowinsky and Donehower, 1991). Docetaxel is an active drug in various solid tumours and is also an attractive agent for incorporation into combination regimens.…”

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A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

et al. 2007

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Pertuzumab represents the first in a new class of targeted therapeutics known as HER dimerisation inhibitors. We conducted a phase Ib study to determine the maximum-tolerated dose, the dose limiting toxicities (DLT), and pharmacokinetic (PK) interaction of docetaxel when administered in combination with pertuzumab. Initially, two dose levels of docetaxel (60 and 75 mg m À2 ) were explored in combination with a fixed dose of 1050 mg of pertuzumab; then two dose levels of docetaxel (75 and 100 mg m À2 ) were explored in combination following a fixed dose of 420 mg of pertuzumab with a loading dose of 840 mg. Both drugs were administered intravenously every 3 weeks. The latter dose of pertuzumab was allowed after an amendment to the original protocol when phase II data suggesting no difference in toxicity or activity between the 2 doses became available. Two patients out of two treated at docetaxel 75 mg m À2 in combination with pertuzumab 1050 mg suffered DLT (grade 3 diarrhoea and grade 4 febrile neutropaenia). Two out of five patients treated at docetaxel 100 mg m À2 in combination with pertuzumab 420 mg with a loading dose of 840 mg suffered DLT (grade 3 fatigue and grade 4 febrile neutropaenia). Stable disease was observed at four cycles in more than half of the patients treated and a confirmed radiological partial response with a 450% decline in PSA in a patient with hormone refractory prostate cancer were observed. There were no pharmacokinetic drug -drug interactions. The recommended phase II dose of this combination was docetaxel 75 mg m À2 and 420 mg pertuzumab following a loading dose of 840 mg.

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The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics

Cited by 311 publications

References 413 publications

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

A phase Ib study of pertuzumab, a recombinant humanised antibody to HER2, and docetaxel in patients with advanced solid tumours

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