Meihua Sui

Nanoparticles for Tumor Targeted Therapies and Their Pharmacokinetics

Various types of nanoparticles, such as liposomes, polymeric micelles, dendrimers, superparamagnetic iron oxide crystals, and colloidal gold, have been employed in targeted therapies for cancer. Both passive and active targeting strategies can be utilized for nano-drug delivery. Passive targeting is based on the enhanced permeability and retention (EPR) effect of the vasculature surrounding tumors. Active targeting relies on ligand-directed binding of nanoparticles to receptors expressed by tumor cells. Release of loaded drugs from nanoparticles may be controlled in response to changes in environmental condition such as temperature and pH. Biodistribution profiles and anticancer efficacy of nano-drugs in vivo would be different depending upon their size, surface charge, PEGylation and other biophysical properties. This review focuses on the recent development of nanoparticles for tumor targeted therapies, including physicochemical properties, tumor targeting, control of drug release, pharmacokinetics, anticancer efficacy and safety. Future perspectives are discussed as well.

Cell Cycle–Dependent Antagonistic Interactions between Paclitaxel and γ-Radiation in Combination Therapy

Purpose: The promising clinical activity of paclitaxel, a naturally occurring antimicrotubule agent, has promoted considerable interest in combining this drug with radiation therapy, but it remains unclear whether such a combination would increase the therapeutic efficacy. This study is to assess the potential interactions between paclitaxel and γ-radiation against human tumor cells in vitro. Experimental Design: Paclitaxel and γ-radiation were administered in three different sequences designated as pre-radiated, co-radiated, and post-radiated to BCap37 (human breast cancer cell line) and KB (human epidermoid carcinoma cell line) cells. The cytotoxic interactions between and mutual influences of these two agents on their antitumor activities were analyzed by a series of assays including cytotoxic, morphological, and biochemical examinations. Results: The combination of paclitaxel and γ-radiation did not produce a synergistic or additive effect. Instead, the overall in vitro cytotoxicity of these combinations was much lower than that of paclitaxel treatment alone. DNA fragmentation and flow cytometric assays showed that the addition of γ-radiation interfered with paclitaxel-induced apoptosis. Further analyses indicated that the addition of γ-radiation resulted in a transient or prolonged cell cycle arrest at G2 phase, which likely prevented the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. In addition, biochemical examinations revealed that γ-radiation inhibited paclitaxel-induced IκBα degradation and bcl-2 phosphorylation and increased the protein levels of cyclin B1 and inhibitory phosphorylation of p34cdc2. Conclusions: Our results suggest that γ-radiation might specifically block the cell cycle at G2 phase, which in turn prevents the cytotoxic effects of paclitaxel on both mitotic arrest and apoptosis. Therefore, it eventually results in a cell cycle-dependent antagonistic effect on the antitumor activity of paclitaxel. This finding may be relevant to the clinical application of combination therapy with paclitaxel and radiation.

The potential biomarkers in predicting pathologic response of breast cancer to three different chemotherapy regimens: a case control study

BackgroundPreoperative chemotherapy (PCT) has become the standard of care in locally advanced breast cancer. The identification of patient-specific tumor characteristics that can improve the ability to predict response to therapy would help optimize treatment, improve treatment outcomes, and avoid unnecessary exposure to potential toxicities. This study is to determine whether selected biomarkers could predict pathologic response (PR) of breast tumors to three different PCT regimens, and to identify a subset of patients who would benefit from a given type of treatment.Methods118 patients with primary breast tumor were identified and three PCT regimens including DEC (docetaxel+epirubicin+cyclophosphamide), VFC (vinorelbine/vincristine+5-fluorouracil+cyclophosphamide) and EFC (epirubicin+5-fluorouracil+cyclophosphamide) were investigated. Expression of steroid receptors, HER2, P-gp, MRP, GST-pi and Topo-II was evaluated by immunohistochemical scoring on tumor tissues obtained before and after PCT. The PR of breast carcinoma was graded according to Sataloffs classification. Chi square test, logistic regression and Cochran-Mantel-Haenszel assay were performed to determine the association between biomarkers and PR, as well as the effectiveness of each regimen on induction of PR.ResultsThere was a clear-cut correlation between the expression of ER and decreased PR to PCT in all three different regimens (p < 0.05). HER2 expression is significantly associated with increased PR in DEC regimen (p < 0.05), but not predictive for PR in EFC and VFC groups. No significant correlation was found between biomarkers PgR, Topo-II, P-gp, MRP or GST-pi and PR to any tested PCT regimen. After adjusted by a stratification variable of ER or HER2, DEC regimen was more effective in inducing PR in comparison with VFC and EFC regimens.ConclusionER is an independent predictive factor for PR to PCT regimens including DEC, VFC and EFC in primary breast tumors, while HER2 is only predictive for DEC regimen. Expression of PgR, Topo-II, P-gp, MRP and GST-pi are not predictive for PR to any PCT regimens investigated. Results obtained in this clinical study may be helpful for the selection of appropriate treatments for breast cancer patients.

Glucocorticoids Selectively Inhibit Paclitaxel-Induced Apoptosis: Mechanisms and Its Clinical Impact

Paclitaxel (Taxol), a naturally occurring antimitotic agent, has shown significant cell-killing activity against tumor cells through induction of apoptosis. The mechanism by which paclitaxel induces cell death is not entirely clear. Recent studies in our laboratory discovered that glucocorticoids selectively inhibited paclitaxel-induced apoptosis without affecting the ability of paclitaxel to induce microtubule bundling and mitotic arrest. This finding implies that apoptotic cell death induced by paclitaxel may occur via a pathway independent of mitotic arrest. Through analyses of a number of apoptosis-associated genes or regulatory proteins, we found that glucocorticoids and paclitaxel possess opposite regulatory role in the NF-kappa B/Ikappa Balpha signaling pathway. Further studies indicate that paclitaxel activates Ikappa B Kinase (IKK), which in turn causes degradation of Ikappa Balpha and activation of NF-kappa B, whereas glucocorticoids antagonize paclitaxel-mediated NF-kappa B activation through induction of Ikappa Balpha synthesis. These results suggest that the NF-kappa B/Ikappa Balpha signaling pathway might play a critical role in the mediation or regulation of paclitaxel-induced cell death. On the other hand, since glucocorticoids (such as dexamethasone) are routinely used in the clinical application of paclitaxel to prevent hypersensitivity reactions and other adverse effects, the inhibitory action of glucocorticoids on paclitaxel-induced apoptosis also raises a clinically relevant question as to whether the pretreatment with glucocorticoids might interfere with the therapeutic efficacy of paclitaxel.

Cell cycle dependent antagonistic interactions between paclitaxel and carboplatin in combination therapy.

The combination of carboplatin and paclitaxel is widely used to treat multiple solid tumors including ovarian, lung and breast cancer. Usually these drugs are given simultaneously with little regard to the importance of scheduling to obtain a maximal response. To investigate the importance of sequencing, the human breast Bcap37 and ovarian OV2008 cancer cell lines were exposed to carboplatin and paclitaxel in three different sequences: 1) pretreatment with paclitaxel followed by carboplatin; 2) pretreatment of carboplatin followed by paclitaxel and 3) simultaneous treatment with these two agents. The combination of carboplatin and paclitaxel resulted in antagonistic interactions when tumor cells were exposed to carboplatin prior to paclitaxel or exposed to the two drugs simultaneously, but there was little antagonistic interaction observed when paclitaxel was administered before carboplatin. Biochemical examination revealed that pretreatment or cotreatment of carboplatin inhibited paclitaxel-induced IκBα degradation and bcl-2 phosphorylation. Further analyses demonstrated that carboplatin could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel was administered before carboplatin. These results indicate that the interaction between paclitaxel and carboplatin is highly schedule dependent. The optimal schedule for this combination is sequential exposure of paclitaxel followed by carboplatin.

The Role of Estrogen and Estrogen Receptors in Chemoresistance

Drug resistance is one of the major obstacles limiting the success of cancer chemotherapy. Biological mechanisms contributing to drug resistance may be present de novo and related to inherent features or may be raised after exposure to anticancer drugs. In recent years, both clinical observations and experimental studies suggested that steroid hormones and their receptors might also affect the therapeutic efficacy of antineoplastic drugs. Estrogens and estrogen receptors (ER) are well-known for their critical roles in the development and progression of breast tumors. It has long been known that breast tumors expressing ERα protein (ERα+) behave in a fundamentally different fashion than ERα-negative (ERα-) tumors with regard to their responses to hormonal therapy. Data obtained from both laboratory and clinical investigations suggested that some chemotherapeutic agents are clearly less effective in ERα+ tumors than ERα- tumors, although the mechanisms of ERα-mediated chemoresistance are not entirely clear. Moreover, recent studies from our laboratory and others demonstrated that the combination of antiestrogenic agents with chemotherapeutic drugs is of significant therapeutic benefit in ERα+ breast cancer over chemotherapy alone. In addition, the ERα-derived peptides, microRNAs specifically targeting ERα, as well as agents targeting estrogen-related receptors (ERRs) may hold promise to sensitize ERα+ breast tumors to chemotherapy. Considering that ERs are expressed in ˜ 65% of human breast cancer, the ERα-mediated chemoresistance has become a big challenge for clinical treatment. The hope to overcome this drug resistance relies on further clarification of specific pathways or molecules contributing to the resistance. More exhaustive and systematic studies are essential to reach deeper understandings on the underlying mechanisms and to develop novel approaches to sensitize ERα+ breast tumors to chemotherapy.

Different administration strategies with paclitaxel induce distinct phenotypes of multidrug resistance in breast cancer cells

Both dose-dense and dose-escalation chemotherapy are administered in clinic. By approximately imitating the schedules of dose-dense and dose-escalation administration with paclitaxel, two novel multidrug resistant (MDR) cell lines Bads-200 and Bats-72 were successfully developed from drug-sensitive breast cancer cell line BCap37, respectively. Different from Bads-200, Bats-72 exhibited stable MDR and significantly enhanced migratory and invasive properties, indicating that they represented two different MDR phenotypes. Our results showed that distinct phenotypes of MDR could be induced by altered administration strategies with a same drug. Administrating paclitaxel in conventional dose-escalation schedule might induce recrudescent tumor cells with stable MDR and increased metastatic capacity.

Combination of gemcitabine antagonizes antitumor activity of paclitaxel through prevention of mitotic arrest and apoptosis.

Paclitaxel, the first member of taxanes, is one of the most active chemotherapeutic agents developed in the last decade for the treatment of advanced breast cancer and many other types of solid tumors. The promising clinical activity of paclitaxel has also promoted considerable interest in combining this drug with other antitumor agents. In this study, we assessed the cytotoxic interaction between paclitaxel and gemcitabine administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, DNA fragmentation, and flow cytometric analyses, we found that gemcitabine could significantly antagonize the cytotoxic effects of paclitaxel when tumor cells were exposed to the two drugs simultaneously or exposed to gemcitabine before paclitaxel. However, there was little antagonistic interaction observed when paclitaxel was administered before gemcitabine. Further analyses demonstrated that gemcitabine could significantly interfere with the cytotoxic effects of paclitaxel on both mitotic arrest and apoptotic cell death unless paclitaxel is administered before gemcitabine. In addition, biochemical examinations revealed that pretreatment or cotreatment of gemcitabine inhibited paclitaxel-induced IκBα degradation and bcl-2 phosphorylation that are believed to play critical roles in the signal pathways leading to apoptotic cell death. These results indicate that the interaction between paclitaxel and gemcitabine is highly schedule dependent. Exposure of tumor cells to gemcitabine before paclitaxel or two drugs simultaneously could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to paclitaxel followed by gemcitabine.

G2 checkpoint abrogator abates the antagonistic interaction between antimicrotubule drugs and radiation therapy

BACKGROUND AND PURPOSE We previously demonstrated that radiation may arrest tumor cells at G2 phase, which in turn prevents the cytotoxicity of antimicrotubule drugs and results in antagonistic interaction between these two modalities. Herein we tested whether G2 abrogators would attenuate the above antagonistic interaction and improve the therapeutic efficacy of combination therapy between radiation and antimicrotubule drugs. MATERIALS AND METHODS Breast cancer BCap37 and epidermoid carcinoma KB cell lines were administered with radiation, UCN-01 (a model drug of G2 abrogator), paclitaxel or vincristine, alone or in combinations. The antitumor activities of single and combined treatments were analyzed by a series of cytotoxic, apoptotic, cell cycle, morphological and biochemical assays. RESULTS UCN-01 significantly enhanced the cytotoxicity of radiation, antimitotic drugs, and their combined treatments in vitro. Further investigations demonstrated that UCN-01 attenuated radiation-induced G2 arrest, and subsequently repressed the inhibitory effect of radiation on drug-induced mitotic arrest and apoptosis. CONCLUSIONS This is the first report demonstrating that G2 checkpoint abrogation represses the inhibitory effect of radiation on antimicrotubule drugs, which may be implicated in cancer combination therapy. Considering that G2 abrogators are under extensive evaluation for cancer treatment, our findings provide valuable information for this class of promising compounds.

Fulvestrant reverses doxorubicin resistance in multidrug-resistant breast cell lines independent of estrogen receptor expression

Drug resistance, a major obstacle to successful cancer chemotherapy, frequently occurs in recurrent or metastatic breast cancer and results in poor clinical response. Fulvestrant is a new type of selective estrogen receptor (ER) downregulator and a promising endocrine therapy for breast cancer. In this study, we evaluated the combination treatment of fulvestrant and doxorubicin in ER-negative multidrug-resistant (MDR) breast cancer cell lines Bads-200 and Bats-72. Fulvestrant potentiated doxorubicin-induced cytotoxicity, apoptosis and G2/M arrest with upregulation of cyclin B1. It functioned as a substrate for P-glycoprotein (P-gp) without affecting its expression. Furthermore, fulvestrant not only restored the intracellular accumulation of doxorubicin but also relocalized it to the nuclei in Bats-72 and Bads-200 cells, which may be another potential mechanism of reversal of P-gp mediated doxorubicin resistance. These results indicated that the combination of fulvestrant and doxorubicin-based chemotherapy may be feasible and effective for patients with advanced breast cancer.