Susan E. Bates

Bio: Susan E. Bates is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Drug resistance & ATP-binding cassette transporter. The author has an hindex of 14, co-authored 15 publications receiving 7788 citations.

Multidrug resistance in cancer: role of ATP–dependent transporters

Abstract: Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.

The Role of ABC Transporters in Clinical Practice

Abstract: Drug resistance remains one of the primary causes of suboptimal outcomes in cancer therapy. ATP-binding cassette (ABC) transporters are a family of transporter proteins that contribute to drug resistance via ATP-dependent drug efflux pumps. P-glycoprotein (P-gp), encoded by the MDR1 gene, is an ABC transporter normally involved in the excretion of toxins from cells. It also confers resistance to certain chemotherapeutic agents. P-gp is overexpressed at baseline in chemotherapy-resistant tumors, such as colon and kidney cancers, and is upregulated after disease progression following chemotherapy in malignancies such as leukemia and breast cancer. Other transporter proteins mediating drug resistance include those in the multidrug-resistance-associated protein (MRP) family, notably MRP1, and ABCG2. These transporters are also involved in normal physiologic functions. The expressions of MRP family members and ABCG2 have not been well worked out in cancer. Increased drug accumulation and drug resistance reversal with P-gp inhibitors have been well documented in vitro, but only suggested in clinical trials. Limitations in the design of early resistance reversal trials contributed to disappointing results. Despite this, three randomized trials have shown statistically significant benefits with the use of a P-gp inhibitor in combination with chemotherapy. Improved diagnostic techniques aimed at the selection of patients with tumors that express P-gp should result in more successful outcomes. Further optimism is warranted with the advent of potent, nontoxic inhibitors and new treatment strategies, including the combination of new targeted therapies with therapies aimed at the prevention of drug resistance.

Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells

Abstract: A disparity was noted in the transport of rhodamine 123 among nine MXR/BCRP/ABCP-overexpressing cells studied; all demonstrated mitoxantrone transport, whereas only two effluxed rhodamine 123. When the MXR/BCRP/ABCP gene was sequenced in the cell lines studied, differences were noted at amino acid 482, predicted to be at the start of the third transmembrane domain. Sequencing genomic DNA revealed wild-type MXR/BCRP/ABCP to have an arginine at position 482. Cells having a threonine or glycine at position 482 were able to efflux rhodamine 123, whereas cells having an arginine were not. A vaccinia virus expression system confirmed that rhodamine as well as doxorubicin efflux is observed with R482T or R482G but not with the wild-type R482; all three MXR/BCRP/ABCP forms transported mitoxantrone. Cross-resistance studies suggest that, compared with wild-type MXR/BCRP/ABCP, cells having an R482T mutation have higher anthracycline resistance, whereas an R482G mutation seems to confer relatively less resistance to SN-38 and topotecan. These results suggest that amino acid 482 has a crucial role in MXR/BCRP/ABCP function and that mutation of a single amino acid residue significantly changes substrate specificity, thus altering the drug resistance phenotype.

Strategies for reversing drug resistance.

Abstract: Drug resistance, intrinsic or acquired, is a problem for all chemotherapeutic agents. In this review, we examine numerous strategies that have been tested or proposed to reverse drug resistance. Included among these strategies are approaches targeting the apoptosis pathway. Although the process of apoptosis is complex, it provides several potential sites for therapeutic intervention. A variety of targets and approaches are being pursued, including the suppression of proteins inhibiting apoptosis using antisense oligonucleotides (ASOs), and small molecules targeted at proteins that modulate apoptosis. An alternate strategy is based on numerous studies that have documented methylation of critical regions in the genome in human cancers. Consequently, efforts have been directed at re-expressing genes, including genes that affect drug sensitivity, using 5-azacytidine and 2'-deoxy-5-azacytidine (DAC, decitabine) as demethylating agents. While this strategy may be effective as a single modality, success will most likely be achieved if it is used to modulate gene expression in combination with other modalities such as chemotherapy. At a more basic level, attempts have been made to modulate glutathione (GSH) levels. Owing to its reactivity and high intracellular concentrations, GSH has been implicated in resistance to several chemotherapeutic agents. Several approaches designed to deplete intracellular GSH levels have been pursued including the use of buthionine-(S,R)-sulfoxime (BSO), a potent and specific inhibitor of gamma-glutamyl cysteine synthetase (gamma-GCS), the rate-limiting step in the synthesis of GSH, a hammerhead ribozyme against gamma-GCS mRNA to downregulate specifically its levels and targeting cJun expression to reduce GSH levels. Alternate strategies have targeted p53. The frequent occurrence of p53 mutations in human cancer has led to the development of numerous approaches to restore wild-type (wt) p53. The goals of these interventions are to either revert the malignant phenotype or enhance drug sensitivity. The approach most extensively investigated has utilized one of several viral vectors. An alternate approach, the use of small molecules to restore wt function to mutant p53, remains an option. Finally, the conceptually simplest mechanism of resistance is one that reduces intracellular drug accumulation. Such reduction can be effected by a variety of drug efflux pumps, of which the most widely studied is P-glycoprotein (Pgp). The first strategy utilized to inhibit Pgp function relied on the identification of non-chemotherapeutic agents as competitors. Other approaches have included the use of hammerhead ribozymes against the MDR-1 gene and MDR-1-targeted ASOs. Although modulation of drug resistance has not yet been proven to be an effective clinical tool, we have learned an enormous amount about drug resistance. Should we succeed, these pioneering basic and clinical studies will have paved the road for future developments.

Rhodamine efflux patterns predict p-glycoprotein substrates in the national cancer institute drug screen

Abstract: Fifty-eight cell lines in the National Cancer Institute drug screen were analyzed for their ability to efflux the fluorescent dye rhodamine 123 as a functional assay for P-glycoprotein (Pgp). Using flow cytometry, the rhodamine fluorescence was measured for each cell line under four incubation conditions, i.e., after accumulation in the presence or absence of the Pgp antagonist cyclosporin A and after efflux in rhodamine-free medium in the presence or absence of cyclosporin A. The results in some cell lines were compatible with Pgp-mediated efflux. There was a significant correlation between mdr-1 expression and rhodamine efflux in the 58 cell lines (r = 0.788, p = 0.0001). Using the rhodamine efflux data as a seed for COMPARE analysis with the cytotoxicity data on > 30,000 compounds in the National Cancer Institute drug screen database, hundreds of compounds with high correlation coefficients were identified. Selected compounds were tested for reversal of cross-resistance in a multidrug-resistant cell line. A high degree of reversibility, up to 10,000-fold, for some of the compounds was noted in the presence of the Pgp antagonist PSC 833. This finding suggested that compounds with predominately Pgp-mediated resistance were being identified. Using these compounds as seeds for COMPARE analysis against a more restricted database of 187 standard agents, a series of standard compounds were repeatedly identified as having high correlation coefficients with the newly identified Pgp substrates. These standard agents, including phyllanthoside, bisantrene, and homoharringtonine, constitute an mdr-1 profile. New agents identified as being highly correlated with these compounds may benefit from clinical trials with Pgp antagonists.

Nanocarriers as an emerging platform for cancer therapy

Abstract: Nanotechnology has the potential to revolutionize cancer diagnosis and therapy. Advances in protein engineering and materials science have contributed to novel nanoscale targeting approaches that may bring new hope to cancer patients. Several therapeutic nanocarriers have been approved for clinical use. However, to date, there are only a few clinically approved nanocarriers that incorporate molecules to selectively bind and target cancer cells. This review examines some of the approved formulations and discusses the challenges in translating basic research to the clinic. We detail the arsenal of nanocarriers and molecules available for selective tumour targeting, and emphasize the challenges in cancer treatment.

Multidrug resistance in cancer: role of ATP–dependent transporters

Abstract: Chemotherapeutics are the most effective treatment for metastatic tumours. However, the ability of cancer cells to become simultaneously resistant to different drugs--a trait known as multidrug resistance--remains a significant impediment to successful chemotherapy. Three decades of multidrug-resistance research have identified a myriad of ways in which cancer cells can elude chemotherapy, and it has become apparent that resistance exists against every effective drug, even our newest agents. Therefore, the ability to predict and circumvent drug resistance is likely to improve chemotherapy.

Principles of nanoparticle design for overcoming biological barriers to drug delivery

Abstract: Biological barriers to drug transport prevent successful accumulation of nanotherapeutics specifically at diseased sites, limiting efficacious responses in disease processes ranging from cancer to inflammation. Although substantial research efforts have aimed to incorporate multiple functionalities and moieties within the overall nanoparticle design, many of these strategies fail to adequately address these barriers. Obstacles, such as nonspecific distribution and inadequate accumulation of therapeutics, remain formidable challenges to drug developers. A reimagining of conventional nanoparticles is needed to successfully negotiate these impediments to drug delivery. Site-specific delivery of therapeutics will remain a distant reality unless nanocarrier design takes into account the majority, if not all, of the biological barriers that a particle encounters upon intravenous administration. By successively addressing each of these barriers, innovative design features can be rationally incorporated that will create a new generation of nanotherapeutics, realizing a paradigmatic shift in nanoparticle-based drug delivery.

Nanoparticle therapeutics: an emerging treatment modality for cancer

Abstract: Nanoparticles — particles in the size range 1–100 nm — are emerging as a class of therapeutics for cancer. Early clinical results suggest that nanoparticle therapeutics can show enhanced efficacy, while simultaneously reducing side effects, owing to properties such as more targeted localization in tumours and active cellular uptake. Here, we highlight the features of nanoparticle therapeutics that distinguish them from previous anticancer therapies, and describe how these features provide the potential for therapeutic effects that are not achievable with other modalities. While large numbers of preclinical studies have been published, the emphasis here is placed on preclinical and clinical studies that are likely to affect clinical investigations and their implications for advancing the treatment of patients with cancer.

Cancer drug resistance: an evolving paradigm

Abstract: Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.