Abstract Immunology as a science celebrated its bicentenary just before the dawn of the new millennium. In 1796 Jenner reported his finding that inoculation of a young man, James Phipps, with pus obtained from a cowpox lesion (or vaccinia from the latin term ‘vacca’ meaning cow) resulted in protection against human smallpox, a frequently fatal disease. This was the first documented evidence for the effectiveness of ‘vaccination’. Despite Jenner’s firm evidence, the resistance of the Church to his methods meant that smallpox vaccination did not become routine until the twentieth century.
Abstract With advancements in our understanding of the basic mechanisms of oncegenesis and the induction of apoptosis, we have gained a greater appreciation of the critical role cell cycle regulation plays in malignant transformation and in the development of resistance to chemotherapy. Perturbations in the cell cycle are commonly described in carcinogenesis. Furthermore, with our improved understanding of the effects of chemotherapy on normal and cancer ous cells, it is increasingly apparent that the cell cycle also plays a critical role in the development of resistance to chemotherapy. These observations have led to the development of a new class of anticancer therapeutics in clinical development today: specifically, those drugs that target the motors of the cell cycle, the cyclin-dependent kinases (CDKs).
Abstract Cancer is a complex disease with variable phenotypes determined by different genes. Aside from curative surgery in the early stages of cancer, treatment of advanced cancer includes cytotoxics, biologics, or radiation. These modalities affect both tumour and normal tissue, leaving in its wake significant toxicity. The benefits of cytotoxic drugs are determined to different extents by patient biology, absorption, distribution, metabolism, excretion, and by tumour biology. In patients with advanced disease, where the goal is palliative and not curative, the best modern therapies still only benefit the minority in terms of improving response rates and survival and the disease ultimately relapses in a short period of time. This is compounded by toxicity of varying degrees experienced by patients resulting in a low risk-benefit ratio.
Abstract Normal ceJl growth is a strictly regulated process with well-balanced activity between growth-stimulating and growth-inhibiting factors. In tumour cells, mechanisms of growth control are severely altered, shifting the balance towards uncontrolled proliferation. In addition, tumour cells are characterised by resistance against triggers for programmed cell death (apoptosis), growth into adjacent structures and the ability to form metastases. This abnormal situation develops through mutations in genes involved in pivotal cellular processes such as proliferation, differentiation, migration, adhesion, and apoptosis.
Abstract Cytokines are proteins secreted by the ce11s of innate and adaptive immune system and mediate many of the functions of these cells. Cytokines are produced in response to microbes and other antigens, for example, tumour antigens. They stimulate the growth and differentiation of lymphocytes, and activate different effector cells to eliminate microbes and other antigens. Of the many cytokines that currently have been identified, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-a (IFNa), interleukin-2 (IL-2) and interleukin-12 (IL-12) are most advanced in their development in the treatment of cancer.
Abstract T lymphocytes and other immune effectors offer potentially attractive agents with which to treat cancer. They can mediate selective killing of malignant cells that express a molecular repertoire differing from that within normal cells. Immunotherapy for malignancy is more difficult than vaccination against infections and remains largely an experimental modality.
Abstract The concept of vaccinating patients against their cancers has advanced over time (as outlined in Chapter 2). What started out as hypotheses, was succeeded with empirical studies and observations in the laboratory and dinic, and currently represents an established scientific discipline with constantly expanding frontiers. Approaches to cancer vaccination can be broadly grouped into two categories:(1) approaches that rely on the whole tumour ceJl or fractions derived from it as the source of immunogen; and(2) approaches that utilise a synthetic immunogen that immunologically mimics a molecule associated with the tumour cell. Such a molecule is called a tumour-associated antigen(s) (TAA).
Abstract The development of gene therapy as a potential therapeutic modality for both inherited and acquired disease has continued to gain momentum and sustained interest among the scientific and medical community. The number of gene therapy clinical trials conducted in the UK and elsewhere has risen year on year since its infancy in the early 1990s. In the UK, the Gene Therapy Advisory Committee (GTAC) has approved 96 trials in its I I-year history, 11 in 2004 compared with 3 in 1993 (GTAC 2005; Nevin 1998).
Abstract As you certainly know, and if not it will become apparent from a reading of the subsequent chapters of this book, cancer is a genetic disease and a disease of cells. Commonly, cancer is described as a disease of unregulated, or dysregulated, cell growth. Significantly, we will see that cancer is a disease of cellular control systems. Before we look at these systems in more detail, it may be useful to consider what cells are.
Abstract Cellular signalling is critical for embryonic development, tissue differentiation, and cellular response to the environment. The complex signalling network is initiated in large part by extracellular ligands, including growth factors and other various stimuli, which interact with membrane receptors and then activate a cascade of intracellular molecules known as secondary messengers that ultimately are responsible for the cellular response. De-regulated cellular signalling is a common feature of cancer cells, which leads to uncontrolled proliferation and increased survival. Identification of the molecular abnormalities in cancer cells, particularly key proteins that play a role in abnormal cell proliferation, have led to the development of anticancer strategies that disrupt the synthesis or function of these proteins. As a large body of data about the cellular signalling network is accumulating, the complexities related to these strategies are being recognised and it is becoming increasingly clear that the redundancies in cellular signalling are very important in cancer cells, making approaches to therapy that involve any single pathway more challenging.
Abstract An introduction of this kind, in this kind of book, is where the editors get to claim that the book you have in your hands is the book they set out to produce. Through a winning combination of intelligent choices, hard work, and thoughtful editing, the goals they set for themselves at the outset have all been reached, if not surpassed. Perhaps we will get to that introduction shortly, but first let’s talk about Singin in the rain (bear with us, we hope to make a serious point).
Abstract The extracellular matrix (ECM) is an elaborate network of macromolecules that surrounds the cells of the body. Ultrastructurally, it consists of two identifiable domains, one that envelops cell sheets and the interstitial matrix, and a second, more condensed layer, termed the basement membrane, which is formed adjacent to the epithelial cells (Bosman & Stamenkovic 2003). The ECM is intricate and adaptable, serving both as structural support for tissues and as a complex microenvironment critical for modulating a wide variety of cell behaviours, from cell signalling, adhesion, and migration, to cellular proliferation, differentiation, and apoptosis. The architecture of the ECM is characterised by a three-dimensional collagen scaffold to which numerous specialised macromolecules adhere. It is a dynamic structure, subject to constant remodelling through the actions of different secreted and cell-associated proteolytic enzymes. This remodelling process allows tissues to respond to physiological changes such as development, pregnancy, growth, and wound repair.
Abstract In contrast to what you will read elsewhere in this book, I do not want to say here that cancer is a disease of cells: it is not. For our purposes, cancer is a disease of people. It is the potential to extend and save human lives that drives our interest in cancer and at some point in our research we are bound to attempt to translate interesting developments in our biological understanding into real therapies for people with cancer.
Abstract The therapeutic potential of monoclonal antibodies (mAbs) was realised a long time before their structure had been explored. It was Paul Ehrlich in the late nineteenth century who developed the idea of a targeted therapy against malignant tumours. Still today, it is fascinating to read his Croonian lecture or the Nobel Prize lecture given in 1908 (see Ehrlich 1900). It took some generations of researchers to reveal the origin and structure of antibodies and then to produce monoclonal antibodies with a defined specificity in significant amounts (Porter 1967; Edelman et al. 1968; Kohler and Milstein 1975). In 1975, Kohler and Milstein published details of the hybridoma technology, which is the fusion of an antigen-specific B-ceJl with an immortal cell-line, resulting in an immortal clone producing the antigen-specific antibody (Kohler and Milstein 1975).
Cancer BiotherapyVol. 10, No. 4 Biotherapy and RadiopharmaceuticalsRobert K. OldhamRobert K. OldhamSearch for more papers by this authorPublished Online:17 Jul 2009https://doi.org/10.1089/cbr.1995.10.251AboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "Biotherapy and Radiopharmaceuticals." , 10(4), p. 251FiguresReferencesRelatedDetails Volume 10Issue 4Jan 1995 To cite this article:Robert K. Oldham.Biotherapy and Radiopharmaceuticals.Cancer Biotherapy.Jan 1995.251-251.http://doi.org/10.1089/cbr.1995.10.251Published in Volume: 10 Issue 4: July 17, 2009PDF download
Subcutaneous administration of low doses of recombinant interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) on an out-patient basis has been reported not to significantly compromise the response frequency compared to intravenous IL-2 in patients with renal cell carcinoma and melanoma. As part of an ongoing program to develop a biotherapeutic concept in patients with colorectal carcinoma (CRC) we studied the clinical effects of such a regimen in 15 patients with metastatic CRC. The daily dose of IL-2 varied between 4.8-14.4 x 10(6) U/m2 and of IFN-alpha between 3-6 x 10(6) U/m2. The cycle length was 6 weeks. The course was repeated every 8 weeks until disease progression. Maximum 4 cycles were administered. Maintenance therapy was given to responding patients once a week every month. No patient showed a major response (CR or PR). Six patients had a stable disease ranging from 3 months to 18 months with a median duration time of 5 months. The median survival of all patients was 13 months. The main adverse reactions were fever, chills, anorexia and shortness of breath. No treatment related deaths occurred. 6/14 patients developed abnormal concentration of serum levels of thyroid hormones. It is concluded that the present treatment schedule using IL-2 and IFN-alpha in advanced CRC seemed not to be of clinical benefit.
This re-evaluation of a pilot study conducted nearly three decades ago (1965-1970), in which serendipity played a central role in favorable responses of hematologic malignancies to the administration of adoptive lymphocytes from both parents, has been motivated by clearer understanding. Temporary remissions marking LAK cell-driven graft-versus-leukemia (GvL) responses were observed in four of seven acute leukemia patients associated with unique self-limited graft-versus-host (GvH) reactions that were NK cell and cytokine related. Retinopathy not previously reported in a GvH setting was a consistent manifestation in these patients. Cure was achieved in an eighth patient with acute lymphoblastic leukemia after she had been given effective chemotherapy, an active role for the adoptive therapy indicated by the occurrence of a week of fever suggesting an abortive GvH reaction. Two of five patients with Hodgkin's disease also experienced favorable responses to parental leukocyte therapy, one exhibiting GvH manifestations almost identical to those seen in the acute leukemia patients when given the adoptive therapy successfully to spur recovery from severe herpes zoster that had interrupted curative radiation therapy. The GvH in the other patient was a more typical one, the key effect being an increase in circulating lymphocytes that may have contributed indirectly to cure with subsequent therapy. These and other attempts to apply GvL responses therapeutically, including those currently in favor, exemplify the shortcomings of partial mitogenic responses to alloactivation, which are dependent on engraftment, limited in scope, excessively toxic, and difficult to control. Treatment with mitogens such as PHA would be a superior alternative because of the abilities of these agents to regulate immune responses by simple modulations of dosage, scheduling, and modes of application.
A growing body of evidence indicate that carotenoids possess anticarcinogenic, anti-mutagenic and immunomodulating effects. Saffron obtained from the dried stigmas of Crocus sativus L., is an important spice, rich in carotenoids, consumed commonly in different parts of the world. Our laboratory first reported the anticancer activity of saffron extract (dimethyl-crocetin) against a wide spectrum of murine tumors and human leukemia cell lines. The present report reviews the role of saffron in serving as a chemopreventive agent in modifying cancer risk. Dose-dependent cytotoxic effect to carcinoma, sarcoma and leukemia cells in vitro were noted. Saffron delayed ascites tumor growth and increased the life span of the treated mice compared to untreated controls by 45-120%. In addition, it delayed the onset of papilloma growth, decreased incidence of squamous cell carcinoma and soft tissue sarcoma in treated mice. Understanding the mechanisms of action of saffron have been solitarily based on their carotenoid-like action. Our results indicated significant inhibition in the synthesis of nucleic acids but not protein synthesis. It appears now that saffron (dimethyl-crocetin) disrupts DNA-protein interactions e.g. topoisomerases II, important for cellular DNA synthesis.
