Drug control of Ara-C-resistant tumor cells

Schabel, Frank M.; Skipper, Howard E.; Trader, M W; Brockman, R. W.; Laster, W R; Corbett, T.H.; Griswold, Daniel P.

doi:10.1002/mpo.2950100713

Cited by 21 publications

(3 citation statements)

References 15 publications

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“…However, patients often develop resistance during the course of treatment (2–7) and the mechanisms that account for such resistance have not been fully identified. Changes in drug influx and efflux, deficiencies in the mismatch repair pathway, and down-regulation of the apoptotic cascade have all been proposed (8–12).…”

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confidence: 99%

Copper Transporter 2 Regulates the Cellular Accumulation and Cytotoxicity of Cisplatin and Carboplatin

Blair

Larson

Safaei

et al. 2009

Clinical Cancer Research

131

104

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Purpose: Copper transporter 2 (CTR2) is known to mediate the uptake of Cu +1 by mammalian cells. Several other Cu transporters, including the influx transporter CTR1 and the two efflux transporters ATP7A and ATP7B, also regulate sensitivity to the platinum-containing drugs. We sought to determine the effect of CTR2 on influx, intracellular trafficking, and efflux of cisplatin and carboplatin. Experimental Design: The role of CTR2 was examined by knocking down CTR2 expression in an isogenic pair of mouse embryo fibroblasts consisting of a CTR1 +/+ line and a CTR1 -/-line in which both CTR1alleles had been deleted. CTR2 levels were determined by quantitative reverse transcription-PCR and Western blot analysis. Cisplatin (DDP) was quantified by inductively coupled plasma mass spectrometry and Results: Deletion of CTR1reduced the uptake of Cu, DDP, and CBDCA and increased resistance to their cytotoxic effects by 2-to 3-fold. Knockdown of CTR2 increased uptake of Cu only in the CTR1 +/+ cells. In contrast, knockdown of CTR2 increased whole-cell DDP uptake and DNA platination in both CTR1+/+ and CTR1 -/-cells and proportionately enhanced cytotoxicity while producing no effect on vesicular accumulation or efflux. A significant correlation was found between CTR2 mRNA and protein levels and sensitivity to DDP in a panel of six ovarian carcinoma cell lines. Conclusions: CTR2 is a major determinant of sensitivity to the cytotoxic effects of DDP and CBDCA. CTR2 functions by limiting drug accumulation, and its expression correlates with the sensitivity of human ovarian carcinoma cell lines to DDP.Platinum-based chemotherapeutic agents have been among the most widely used and effective anticancer agents since the 1970s (1). However, patients often develop resistance during the course of treatment (2 -7) and the mechanisms that account for such resistance have not been fully identified. Changes in drug influx and efflux, deficiencies in the mismatch repair pathway, and down-regulation of the apoptotic cascade have all been proposed (8 -12). To complicate matters, little is known about the intracellular metabolism of platinum-based agents. It is believed that these drugs kill cells through formation of adducts on the purine bases of nuclear DNA (9,13,14); however, it is not clear how the drugs traffic through the cell to reach the nucleus. There is a strong correlation between drug sensitivity and drug accumulation, with DDPresistant cells uniformly accumulating less drug (4, 15 -21).Several studies have provided evidence that the platinumcontaining drugs are taken up, shuttled around the cell, and exported by transporters and chaperones belonging to the Cu homeostasis system. Cells selected for resistance to cisplatin (DDP) are cross-resistant to . CTR1 is a high-affinity plasma membrane Cu transporter. Cu associates with the hCTR1 metal binding motif in the NH 2 -terminal domain and is transported into the cytosol through a channel formed by the hCTR1 trimer (26,27). Cu is then handed off to the various chaperones to...

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confidence: 99%

Copper Transporter 2 Regulates the Cellular Accumulation and Cytotoxicity of Cisplatin and Carboplatin

Blair

Larson

Safaei

et al. 2009

Clinical Cancer Research

131

104

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“…both in man and rodent, that initially drug sensitive tumors become progressively less responsive and ultimately fail to respond during continuous treatment. 64 The main aim of combination chemotherapy is to avoid the consequences of the presence of drug-resistant cells. However, resistance to as many as six separate drugs has been shown to occur in treatment of human or experimental tumors.…”

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confidence: 99%

Sequencing of drugs and radiation. The integrated alternating regimen

Tubiana

Arriagada

Cosset

1985

Cancer

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The association of radiotherapy (RT) and chemotherapy (CT) constitutes one of the main avenues for research in therapeutic oncology. This association has two aims: (1) increase in control rate of primary tumor (this requires either the potentiation of one of the two modalities by the other or the additivity of their effect on tumor cells without a parallel increase in the toxic effects on critical normal tissues); (2) spatial cooperation (RT being used for the control of the primary tumor or of the sanctuaries, and CT for the control of the disseminated disease). In these two strategies, RT and CT should be given up to full doses in order to be effective. The main risk is an increase in the number and severity of the early and late side effects. To circumvent this problem, two possibilities are being explored: (1) use of drugs without serious toxic effects on those critical tissues which are included in the irradiated volume; and (2) avoidance of concomitant administration and introduction of a sufficiently long‐time gap between the completion of one modality and initiation of the other. However, in such sequential treatment, a delay of CT until after the completion of RT, or an interruption of CT cycle during the course of RT, allows the occult metastases to increase in size; a similar delay in initiation of RT is also detrimental, as drugs are often not effective on bulky tumors. Moreover, under CT, the cells which are resistant to the cytotoxic drugs may disseminate and initiate chemoresistant metastases. Taking these disadvantages into account, a treatment protocol was proposed in 1980 in which CT and RT are given alternately, without undue delay. Chemotherapy is started with the usual scheduling of one cycle every month. Radiotherapy courses are interdigitated between CT cycles. Each course is initiated 1 week after interrupting CT and continued until 1 week before beginning the subsequent cycle of chemotherapy, and so on until completion of RT. Such split‐course RT should have an effect on a tumor comparable to that of a conventional fractionation. This protocol has been used on 24 patients with non‐Hodgkin's lymphoma (NHL) of diffuse histology, and 63 patients with small cell carcinoma of the lung. The 2‐year relapse‐free survivals are promising (in clinical stage II NHL of diffuse histology, 75%; and in small cell lung carcinomas, 33%). The early and late tolerances are satisfactory and no untoward complications have been observed.

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“…The need to know the MTD is based on the well ingrained notion that the relationship between dose and cancer cell kill is linear[15] and more must be better. The notion, even though disavowed by the same scientist that first introduced it[16, 17], continues to be very dominant in oncology, even though some oncologists have begun using lower doses of chemotherapy in combination with targeted therapies. [18–21]…”

Section: The Need To Change Clinical Trial Design In Order To Obtain mentioning

confidence: 99%

Future paradigms for precision oncology

et al. 2016

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Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used.

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Drug control of Ara-C-resistant tumor cells

Cited by 21 publications

References 15 publications

Copper Transporter 2 Regulates the Cellular Accumulation and Cytotoxicity of Cisplatin and Carboplatin

Copper Transporter 2 Regulates the Cellular Accumulation and Cytotoxicity of Cisplatin and Carboplatin

Sequencing of drugs and radiation. The integrated alternating regimen

Future paradigms for precision oncology

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