In vitro interactions of a new derivative of spicamycin, KRN5500, and other anticancer drugs using a three-dimensional model

Kanzawa, Fumihiko; Nishio, Kazuto; Fukuoka, Kazuya; Sunami, Toshihiko; Saijo, Nagahiro

doi:10.1007/s002800050907

Cited by 32 publications

(38 citation statements)

References 7 publications

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“…In this method, synergy, additivity, and antagonism are defined as combination effect > 0, combination effect = 0, and combination effect < 0, respectively. The theoretical basis and practical application of the Kanzawa method have been previously described (4,9). Briefly, cytotoxicity data in an 8 Â 8 well matrix format from six replicate plates were entered into a Microsoft Excel (Redmond, WA) spreadsheet and the combination effect was computed.…”

Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia

Shanks

Rizzieri

Flowers

et al. 2005

Clinical Cancer Research

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The DNA antimetabolite gemcitabine is an anticancer agent with shown preclinical and clinical utility and a low toxicity profile. In this study, we sought to identify and optimize drug partners for binary and tertiary combinations with gemcitabine for use in the treatment of acute myelogenous leukemia (AML). Drug interaction was assessed by growth inhibition assay with metabolic end points. The combination index method was used to evaluate combinations of gemcitabine with fludarabine, paclitaxel, chlorambucil, doxorubicin, mitoxantrone, and SN-38 in U937 human AML cells. A three-dimensional method was used to determine the effect of dose ratio and schedule on drug interaction. Mechanisms underlying interactions related to cell cycle effects and apoptosis were assessed by flow cytometric and caspase-3 and -7 assays, respectively. The most synergistic binary combination was gemcitabine + fludarabine.The most synergistic tertiary combination was gemcitabine + fludarabine + paclitaxel, where the interaction was sequence dependent with paclitaxel given before gemcitabine + fludarabine, producing a 2-fold increase in synergy. Cell cycle analysis did not reveal a significant G 2 -M arrest, suggesting that the synergistic effect of paclitaxel in this combination, which produced the greatest caspase activation, might be independent of microtubule stabilization. In contrast, the gemcitabine + fludarabine + mitoxantrone combination was synergistic and schedule independent. Moreover, few ratios of gemcitabine + fludarabine to mitoxantrone were antagonistic, which could be important for clinical translation. In conclusion, synergistic interactions with gemcitabine occurred with several drugs, the most promising being gemcitabine + fludarabine, gemcitabine + fludarabine + paclitaxel, and gemcitabine + fludarabine + mitoxantrone. These findings provided a rationale for clinical trials of gemcitabine + fludarabine and gemcitabine + mitoxantrone where responses were observed in heavily pretreated AML patients.Leukemia is one of the 10 leading causes of cancer deaths in the United States, and acute myelogenous leukemia (AML) is responsible for one third of these deaths (1). Whereas several promising compounds have recently become available, singleagent therapies have been largely unsuccessful in preventing relapse (2). When optimized, combination chemotherapy regimens can offer increased efficacy, decreased toxicity, dose reductions, and decreased drug resistance.Standard induction chemotherapy consists of cytosine arabinoside in combination with an anthracycline antibiotic or anthracenedione (usually daunorubicin, idarubicin, or mitoxantrone). Gemcitabine (2V ,2V -difluorodeoxycytidine) is structurally similar to cytosine arabinoside, but creates DNA damage that is more difficult to repair. In addition, gemcitabine metabolites inhibit ribonucleotide reductase, leading to selfpotentiation of cytotoxic activity (3). Gemcitabine has proven successful against a wide range of tumor types including lung, ovarian, head and nec...

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Section: Methodsmentioning

confidence: 99%

Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia

Shanks

Rizzieri

Flowers

et al. 2005

Clinical Cancer Research

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“…The three-dimensional method of Kanzawa et al 15,48 was used to obtain a global view of the interaction of fludarabine phosphate and DETA-NO in a representative patient. (a) The mean combination effect surface from four separate determinations reveals a continuum of response from highly antagonistic (light) to highly synergistic (dark).…”

Section: Figurementioning

confidence: 99%

Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes

Adams

Levesque²,

Weinberg³

et al. 2001

Leukemia

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“…Gemcitabine in combination with cisplatin has been shown to have either an additive or a synergistic effect in vitro and in vivo in a number of different tumor systems (27)(28)(29)(30). Similarly, treatment with gemcitabine with vindesine was shown to have a synergistic cytotoxic effect when used against a lung cancer cell line (31). Clinical trials of gemcitabine with carboplatin and paclitaxel have shown promising results in patients with non-small cell lung cancer (32).…”

Section: + +mentioning

confidence: 99%

“…With phosphorylation, blocked iKBa remains intact, thereby, blocking NF-KB translocation to the nucleus and subsequent activation of antiapoptotic genes that cause TNF-a insensitivity, thereby allowing the cells to proceed through apoptosis. This iKBa "super-repressor" has also been shown to induce apoptosis in other systems (31,32). The "super-repressor" produces constitutive repression of NF-KBdirected transcription, despite the presence of agonists that normally induce the degradation of iKBa and the nuclear translocation of NF-KB (24).…”

Section: Introduction Introductionmentioning

confidence: 99%

Induced Expression of Androgen Receptor in Androgen Independent Prostate Cancer Cells Using an I kappa B alpha Super Repressor""

Cooper¹,

Pienta²

2002

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Public reporting bunJen for this collection of infomiation is estimated to average 1 hour per response, including the lime for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collecton of information. Send comments regarding this burden estimate or any other aspect of this cdledion of information, including suggestions for reducing this burden to Washington Headquarters Services. TITLE AND SUBTITLE Induced Expression of Androgen Receptor in AndrogenIndependent Prostate Cancer Cells using an iKBa "Super Represser" AUTHOR(S)Carlton R. Cooper, Ph.D. Kenneth Pienta, M.D. FUNDING NUMBERSDAMD17-01-1-0077 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University of Michigan Ann Arbor, Michigan 48109-1274 E-Mail: kpienta@umich.edu PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES)U IntroductionAdvanced prostate cancer continues to kill 32,000 men per year in the United States. Despite strides in obtaining partial, temporary remissions in men with advanced disease through the use of hormones and chemotherapeutic agents, there is no curative therapy for advanced prostate cancer. Most prostate cancers are responsive to androgens, and androgen withdrawal (i.e., surgical or medical castration) is the main form of treatment for advanced (i.e. disseminated) disease.' The failure of primary hormone therapy is attributed to androgenindependent tumor expansion. Although the androgen receptor (AR) is present in these cells, it is nonfunctional.^ These cells have been shown to proliferate by other means, such as insulinlike growth factor (IGF)^ and interleukin-6 (lL-6).'^ Many androgen independent cells survive by acquired resistance to many apoptotic factors, such as TNF-a.^ At this point, there is no clear explanation as to why prostate cancer cells develop androgen independence. We believe that the CBP [CREB (cAMP response element binding protein)-binding protein] may play a critical role.CEP is a transcriptional co-regulator that interacts with different DNA binding proteins and components of the general transcription machinery.^ It is a bridging factor between CREB and the basal transcriptional apparatus.^ In addition to CREB, CBP associates with several other sequence-specific factors, including NF-KB and AR.^ Both NF-KB and AR require CBP for their transactivation.^ However, CBP has a greater affinity for NF-KB than AR.^ As demonstrated in our preliminary data, if NF-KB is active, AR is inactive. NF-KB has already been implicated in the negative regulation of the rat AR gene promoter.NF-KB is held in the cytoplasm by its inhibitor, iKBa. This retention is uncoupled by many extracellular signals, including TNF-a. Through a series of events, TNF-a causes phosphorylation of iKBa which rapidly gets degraded and releases NF-KB. Once released, NF-KB translocates to the nucleus, binds CBP, and begins transcription. We investigated the role of NF-KB in androgen sensitive and insensitive cells and then ap...

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In vitro interactions of a new derivative of spicamycin, KRN5500, and other anticancer drugs using a three-dimensional model

Abstract: These results suggest the usefulness of combinations of KRN5500 with cisplatin, carboplatin or etoposide for chemotherapy for non-small-cell lung cancer.

Cited by 32 publications

References 7 publications

Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia

Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia

Nitric oxide enhancement of fludarabine cytotoxicity for B-CLL lymphocytes

Induced Expression of Androgen Receptor in Androgen Independent Prostate Cancer Cells Using an I kappa B alpha Super Repressor""

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