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This chapter will present a pathophysiologic paradigm that occurs in solid tumors that is characterized by a self-propagating cycle of abnormally regulated angiogenesis, instability in perfusion, and hypoxia. Interactions between tumor and endothelial cells occur during tumor growth and in response to therapy. These interactions are of central importance in establishing codependence that contributes to promotion of cell survival, treatment resistance, enhanced invasion, and metastasis. Results indicate that concurrent targeting of both tumor and endothelial cells may be of central importance in improving treatment responses to both radiation and chemotherapy.

The intratumor microenvironment is intrinsically acidic due mainly to accumulation of lactic acid as a result of increased aerobic and anaerobic glycolysis by the tumor cells. In general, the extracellular pH (pHe) in human tumors is below 7.0, whereas the intracellular pH (pHi) is maintained at neutral range, i.e.,>7.0, by powerful pHi control mechanisms. The low pHe and the significant gradients between pHe and pHi affect markedly the response of tumors to various treatments such as chemotherapy, radiotherapy and hyperthermia. For instance, the acidic pHe increases the cellular uptake of weakly acidic drugs such as cyclophosphamide and cisplatin and thus increases the effect of the drugs, whereas the acidic pHe retards the uptake of weakly basic drug such as doxorubicin and vinblastine, thereby reducing the effect of the drugs. The radiationinduced apoptosis is suppressed by an acidic environment, whereas the hyperthermiainduced cell death is potentiated by an acidic environment. Better understanding of the control mechanisms of pHe and pHi in tumors may lead to device effective treatment strategy of human tumors.

Solid tumor oxygenation is highly heterogeneous, often showing regions of hypoxia that demonstrate oxygen concentrations much lower than those encountered in normal tissues. Tumor hypoxia can cause treatment resistance, resulting in a poorer treatment outcome. In addition, hypoxia forms a part of the pathophysiologic microenvironment that characterizes solid tumors and is involved in disease progression, possibly through alterations in gene expression. This chapter discusses recent research focused on methods of measuring tumor hypoxia accurately and extensively, with the aim of tailoring treatment on an individual patient basis. Examples of therapeutic approaches designed to exploit tumor hypoxia directly or indirectly, are discussed.

Development of therapeutic resistance is intrinsic to the neoplasia and is associated with the complexity, plasticity, and dynamics of the process. Some aspects of drug resistance, such as the ability to repopulate the tumor mass by clonogenic/stem cell subsets or adhesion/aggregation-dependent changes in responsiveness to therapy may be related to genetic tumor progression, genetic instability, and expression of oncogenic proteins. Combinations of cytoreductive agents with oncogene-directed signal transduction inhibitors or angiogenic agents have already produced promising preclinical and clinical results. In the not-too-distant future, refinement and commercialization of pharmacogenomic tests in cancer will enable more-accurate predictions regarding responsiveness of individual patients to new and established agents. These data will also enable understanding of pathways of drug resistance and ways to overcome it.

As cancer treatment moves towards more targeted therapy, there is an increasing need for tools to guide therapy selection and to evaluate response. Biochemical and molecular imaging can complement existing in vitro assay methods and is likely to play a key role in early drug testing and development, as well as future clinical practice. Imaging is ideally suited to assessing the spatial and temporal heterogeneity of cancer and to measure in vivo drug effects. This chapter highlights imaging approaches to guide cancer therapy, focusing on positron emission tomography and on those approaches that have undergone preliminary testing in patients. Examples showing how positron emission tomography imaging can be used to (1) assess the therapeutic target, (2) identify resistance factors, and (3) measure early response are described.

Despite advances in the development of cytotoxic chemotherapies, the fact remains that for most common malignancies, metastatic disease remains incurable. Recent work has suggested that most, if not all, malignancies are driven by a small subpopulation of cells that have stem cell characteristics. These “tumor stem cells” are thought to arise either from normal tissue stem cells or from early progenitor cells through dysregulation of self-renewal pathways. The partial differentiation of cancer stem cells may result in tumor heterogeneity. One of the characteristics of this heterogeneity may be reflected in the resistance of cancer stem cells to cytotoxic chemotherapy. Evidence is presented that current chemotherapeutic regimens selectively target more differentiated cells in tumors, while sparing the tumor stem cell component. This may account for relapse following tumor regression. The mechanisms contributing to the resistance of tumor stem cells to cytotoxic agents may involve increased efficiency of DNA replication and repair mechanisms in stem cells, changes in cell cycle parameters, and the overexpression of antiapoptotic and transporter proteins in these cell populations. The tumor stem cell model of carcinogenesis has fundamental implications for the development of new cancer therapeutic agents, as well as for the design of clinical trials utilizing these agents. Strategies aimed at the targeting of cancer stem cell populations may lead to more effective therapies for the treatment of advanced malignancies.

At Southern Research Institute, a series of in vivo drug-resistant murine P388 leu-kemias were developed for use in the evaluation of crossresistance and collateral sensitivity. These in vivo models have been used for the evaluation of new compounds of potential clinical interest. Crossresistance data coupled with knowledge of the mechanisms of resistance operative in the drug-resistant leukemias may identify useful guides for patient selection for clinical trials of new anti tumor drugs and noncrossresistant drug combinations.

The goal of this chapter is to present several lines of evidence as to the importance of tumor site selection in oncology drug development. Tumor-host interactions differ according to the anatomical location of the tumor and can alter the pharmacodynamic effects of a drug candidate. In some instances, failure of a promising new drug to exhibit efficacy is attributed to drug resistance when instead, the lack of efficacy is a consequence of poor model characterization and selection. Orthotopic models are now presenting us with more-complex models to evaluate the activity of novel drug candidates. We present examples that demonstrate how implant site influences tumor growth kinetics and behavior; as a consequence of these influences, our interpretation of result with early stage drug candidates must be carefully considered. In this chapter, we review a number of studies that support the notion that tumor implantation site represents a critical determinant for the successful and meaningful efficacy evaluation of chemotherapeutic agents.

The EMT6 mammary carcinoma sublines resistant to antitumor alkylating agents were produced by repeated exposure of fresh tumor-bearing hosts to each drug. These tumor lines have been used to extend understanding of drug resistance in a host organism. It is becoming clear as our knowledge of growth factors and cytokines has increased that the proliferation and metabolism of tumor cells, like those of normal cells, are influenced by these naturally occurring growth regulators. Our findings and those of others support the notion that the metabolism of tumor cells can be altered to enhance their survival via mechanisms that involve the autocrine and paracrine functions of growth factors and cytokines. Therapeutic resistance of a tumor in a host organism can evolve by a phenotypic change in the tumor cells that does not confer drug resistance on the isolated tumor cells but, which, through alterations in the handling of the drug by host.

Malignant progression and tumor metastasis is a complex process enabled by various molecular changes occurring in a subpopulation of tumor cells. The metastatic phenotype is associated with the cellular capacity for uncontrolled growth, resistance to apoptosis, high invasive potential, and effective neoangiogenesis. Whereas the contribution of genetic alterations to the metastatic dissemination is not yet clear, because both primary and metastatic tumors often have similar patterns of genetic mutations, the majority of the changes contributing to the metastatic phenotype are controlled epige-netically. In melanoma, the progression toward malignant disease and acquisition of the metastatic phenotype involves loss of activator protein 2 and gain in expression of activating transcription factor 1/cyclic adenosine monophosphate-responsive element-binding protein family transcription factors. Together with upregulation of activating transcription factor 2, Snail, nuclear factor-?B and other transcription factors, this results in deregulation of the expression of cellular adhesion molecules, matrix-degrading enzymes, as well as other factors that enable a complex interaction of tumor cells with extracellular milieu and other cells during malignant progression and metastatic dissemination. Furthermore, because of the need to survive mechanical and immunological challenges, and changing nutritional environment during the dissemination process, metastatic cells are permanently selected for the superior survival capacity. As a result, metastatic cells are commonly characterized by their increased resistance to the chemotherapeutic treatment when compared to primary tumors. Here, we discuss some of the potential mechanisms contributing to drug resistance in melanoma.