[Show abstract][Hide abstract] ABSTRACT: The growth of solid tumors and their regrowth after treatment is dependent upon functional tumor vasculature. Some chemotherapeutic agents have shown anti-angiogenic properties but there are limited studies of the effect of chemotherapy on tumor vasculature. Here we investigate the effect of paclitaxel, 5-fluorouracil (5-FU) and doxorubicin on tumor vasculature in subcutaneous and orthotopic xenografts in mice
The vascular density and percentage of functional blood vessels were evaluated in subcutaneous A431 human vulvar cancer xenografts, and in subcutaneous and orthotopic MCF-7 human breast cancer xenografts, following single doses of paclitaxel, 5-FU or doxorubicin
There was no significant difference in total (CD31+) blood vessels between untreated ectopic and orthotopic MCF-7 tumors, but there was a significantly lower proportion of functional blood vessels in orthotopic tumors. After paclitaxel treatment, there was a decrease in functional tumor vasculature in A431 subcutaneous xenografts, followed by a subsequent rebound. There was a significant decrease in total vascular density on day 12 in A431 tumors following 5-FU or doxorubicin treatment, but no change in the percentage of functional vessels. An increase in functional blood vessels or percentage of functional vasculature was noted in MCF-7 subcutaneous and orthotopic xenografts following chemotherapy treatment
There are differences in the vasculature and microenvironment of ectopic and orthotopic xenografts in mice. Anti-tumor effects of chemotherapy may be due, in part, to effects on tumor vasculature and may vary in different tumor models.
BMC Cancer 12/2015; 15(1):1091. DOI:10.1186/s12885-015-1091-6 · 3.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phase III randomized controlled trials (RCT) in oncology fail to lead to registration of new therapies more often than RCTs in other medical disciplines. Most RCTs are sponsored by the pharmaceutical industry, which reflects industry's increasing responsibility in cancer drug development. Many preclinical models are unreliable for evaluation of new anticancer agents, and stronger evidence of biologic effect should be required before a new agent enters the clinical development pathway. Whenever possible, early-phase clinical trials should include pharmacodynamic studies to demonstrate that new agents inhibit their molecular targets and demonstrate substantial antitumor activity at tolerated doses in an enriched population of patients. Here, we review recent RCTs and found that these conditions were not met for most of the targeted anticancer agents, which failed in recent RCTs. Many recent phase III RCTs were initiated without sufficient evidence of activity from earlyphase clinical trials. Because patients treated within such trials can be harmed, they should not be undertaken. The bar should also be raised when making decisions to proceed from phase II to III and from phase III to marketing approval. Many approved agents showed only better progression-free survival than standard treatment in phase III trials and were not shown to improve survival or its quality. Introduction of value-based pricing of new anticancer agents would dissuade the continued development of agents with borderline activity in early-phase clinical trials. When collaborating with industry, oncologists should be more critical and better advocates for cancer patients.
Clinical Cancer Research 10/2015; 21(20):4552-4560. DOI:10.1158/1078-0432.CCR-15-0124 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined effects of the PPI, lansoprazole, to modify the activity of doxorubicin. To gain insight into mechanisms, we studied effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole displayed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Cancer Science 07/2015; DOI:10.1111/cas.12756 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug resistance can occur at the individual cellular level or as a result of properties of the tumor microenvironment. The convoluted vasculature within tumors results in robustly proliferating well-nourished cells located proximal to functional blood vessels and regions of slowly proliferating (often hypoxic) cells located distal to functional blood vessels. Irregular blood flow and large distances between functional blood vessels in solid tumors lead to poor drug distribution within them such that cells distal from functional blood vessels are exposed to ineffective concentrations of drug, resulting in therapeutic resistance. Strategies to improve or complement the distribution of anticancer drugs within tumors hold promise for increasing antitumor effects without corresponding increases in normal tissue toxicity. In particular, use of hypoxia-targeted agents and modulation of autophagy have shown promising results in enhancing the distribution of drug activity within solid tumors and hence antitumor efficacy. In this review, we describe causes of resistance to chemotherapy that relate to the microenvironment of solid tumors and the potential to improve antitumor effects by countering such mechanisms of resistance.
The Cancer Journal 07/2015; 21(4):254-62. DOI:10.1097/PPO.0000000000000131 · 4.24 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The mechanisms underlying the favourable prognosis of androgen receptor (AR) expression in breast cancer are unknown.
The associations between the 21-gene recurrence score (RS), AR, grade, mitotic score, Ki-67 and estrogen receptor (ER) and progesterone receptor (PgR) expression were explored in sequential women with lymph node-negative, ER-positive and HER2-negative breast cancer. Statistical significance of this exploratory study was defined as p<0.10.
Analysis comprised 70 women. Most tumours had high AR expression (97% had scores >3). Median RS was 15 (range 1-53). AR expression showed a minimally significant positive correlation with ER (R=0.37), but no correlation with Ki-67 (R=-0.18). In univariable analysis, AR (p=0.01), ER (p<0.001) and PgR (p<0.001) had significant negative associations with RS. Ki-67 (p=0.16), grade (p=0.40) and mitotic score (p=0.23) showed no association with RS. Multivariable analysis showed similar associations.
AR is associated with lower RS, but not with Ki-67.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
[Show abstract][Hide abstract] ABSTRACT: Much progress has been made in research for prostate cancer in the past decade. There is now greater understanding for the genetic basis of familial prostate cancer with identification of rare but high-risk mutations (eg, BRCA2, HOXB13) and low-risk but common alleles (77 identified so far by genome-wide association studies) that could lead to targeted screening of patients at risk. This is especially important because screening for prostate cancer based on prostate-specific antigen remains controversial due to the high rate of overdiagnosis and unnecessary prostate biopsies, despite evidence that it reduces mortality. Classification of prostate cancer into distinct molecular subtypes, including mutually exclusive ETS-gene-fusion-positive and SPINK1-overexpressing, CHD1-loss cancers, could allow stratification of patients for different management strategies. Presently, men with localised disease can have very different prognoses and treatment options, ranging from observation alone through to radical surgery, with few good-quality randomised trials to inform on the best approach for an individual patient. The survival of patients with metastatic prostate cancer progressing on androgen-deprivation therapy (castration-resistant prostate cancer) has improved substantially. In addition to docetaxel, which has been used for more than a decade, in the past 4 years five new drugs have shown efficacy with improvements in overall survival leading to licensing for the treatment of metastatic castration-resistant prostate cancer. Because of this rapid change in the therapeutic landscape, no robust data exist to inform on the selection of patients for a specific treatment for castration-resistant prostate cancer or the best sequence of administration. Moreover, the high cost of the newer drugs limits their widespread use in several countries. Data from continuing clinical and translational research are urgently needed to improve, and, crucially, to personalise management.
The Lancet 06/2015; DOI:10.1016/S0140-6736(14)61947-4 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Autophagy allows recycling of cellular components and may facilitate cell survival after chemotherapy. Pantoprazole inhibits proton pumps and is reported to inhibit autophagy. Here we evaluate the effects of pantoprazole to modify cytotoxicity of the anticancer drug docetaxel, and underlying mechanisms.
Effects of docetaxel±pantoprazole were studied against wild-type and autophagy-deficient PC3 cells and against four human xenografts. Effects of pantoprazole on autophagy were evaluated by quantifying LC3-I, LC3-II and p62 proteins in western blots, and by fluorescent microscopy of cells transfected with RFP-GFP-LC3. The distribution of drug effects and of autophagy was quantified in tumour sections in relation to blood vessels and hypoxia by immunohistochemistry using γH2AX, cleaved caspase-3, Ki67 and LC3/ p62.
Pantoprazole increased the toxicity of docetaxel in vitro, increased docetaxel-induced expression of γH2AX and cleaved caspase-3, and decreased Ki67 in tumour sections. Pantoprazole increased growth delay of four human xenografts of low, moderate and high sensitivity to docetaxel, with minimal increase in toxicity. Docetaxel led to increased autophagy throughout tumour sections. Pantoprazole inhibited autophagy, and effects of pantoprazole were reduced against genetically modified cells with decreased ability to undergo autophagy.
Autophagy is a mechanism of resistance to docetaxel chemotherapy that may be modified by pantoprazole to improve therapeutic index.
British Journal of Cancer 02/2015; 112(5). DOI:10.1038/bjc.2015.17 · 4.84 Impact Factor