Acute Myeloid Leukemia: Causes and Treatment Strategies

Acute Myeloid Leukemia: Causes and Treatment Strategies Pathology Acute myeloid leukemia is a disease that primarily afflicts adults. The likelihood of being diagnosed with AML increases with age; the median age of diagnosis is 65 with very few cases reported in those under the age of 40 [4]. Several risk factors have been associated with increased incidence of AML including: Li-Fraumeni disease, Klinefelter’s syndrome, radiation exposure, chemotherapy, and chemicals (benzene, herbicides, etc) (See supplementary figure S.1) [4]. However, the initiation of AML is a multistep process and can be the result many different genetic aberrations [4][5]. Therefore, the aforementioned risk factors do not account for all cases of AML [4]. Acute myelogenous leukemia is the result of oncogene-driven accumulation of immature myeloblasts within the bone marrow [5]. Myeloblasts are progenitor cells, which will ultimately give rise to neutrophils, basophils, eosinophils, and mast cells (collectively known as the granulocytes) [6]. In AML, the genes that govern proper differentiation of myeloblasts into one of the aforementioned cell types are mutated. This prevents differentiation and leads to a buildup of myeloblasts within the marrow [5]. The clinical consequences of myeloblast buildup are marrow failure leading to low white-blood cell count, low red-blood cell count, and insufficient levels of clotting factors [5]. Therefore, clinical symptoms are depressed immune function, anemia, and continued hemorrhaging. The molecular pathogenesis of AML (and all cancers) begins with the acquisition of genetic abnormalities. There are two models that describe how these acquisitions arise. The conventional model of cancer cell initiation proposes that the cell gradually acquires certain mutations to genes involved in mitotic signaling (KRAS or APC) and tumor suppression (P53), thereby allowing the cell to divide uncontrollably [7]. However, Recent work by Stephens et al. [8] showed that multiple mutations can be induced in a â€Å"one off† event by the random shattering and re-ligation of one or more chromosomes [8]. They termed this event â€Å"Chromothripsis† [8]. Chromothripsis results in massive translocations and changes to copy number state, but is distinct from the conventional model of cancer cell initiation by the presence of large-scale inter-chromosomal rearrangements [8]. Thus, the chromothripsis model differs from its conventional counterpart in the time taken for the cell t o reach malignancy and the scale to which the genome is altered. Chromothripsis is observed in a portion of AML cases; Rausch et al. [9] found nearly half of the AML cohort showed chromosomal rearrangements consistent with chromothripsis [9]. This shows that, accumulation of the necessary mutations that drive AML may occur by more than one mechanism. By either mechanism of AML initiation, myeloblasts lose the ability to differentiate. The molecular pathogenesis commonly shows two frequent chromosomal aberrations – a translocation between chromosome 8 and 21, and an inversion of chromosome 16 [5]. These changes affect two genes crucial for myeloid differentiation (CBF1ÃŽ ± and CBF1ÃŽ ²) [5]. The effect of the inversion and translocation results in a gene chimera, which is translated into a protein that interferes with proper CBF1ÃŽ ± and CBF1ÃŽ ² function [5]. However, these specific chromosomal alterations are not observed in every case of AML. DNA-damage inducing agents like radiation or certain chemicals, may cause aberrations to chromosome 5 and 7, which has also been implicated in the initiation of AML [5]. This shows that there are several factors involved in proper myeloid differentiation and that interference to any of them may result in AML. Visual differentiation of healthy myeloblasts from leukemic myeloblasts can be challenging. Myeloblasts should contain 3 5 nucleoli, which are full of uncondensed chromatin [6]. Some leukemic myeloblasts may show more than 3 – 5 nucleoli [5]. Also, they do not normally contain granules, however, leukemic myeloblasts may have granules, which can serve as a potential marker for diagnosis [5]. It is important to stress that these morphological changes may not appear in all cases of AML. Therefore, prognosis is confirmed by the presence of greater than 20% myeloblasts in bone marrow biopsy [5]. Treatment There are different avenues for treating AML. Treatment may include supportive care (in advanced cases), chemotherapy, and stem cell transplantation. However, chemotherapy is the most common and effective method of treatment [3]. When medicinal chemists began isolating antibiotics produced from bacteria in search of potential leads for drug design, Aurelio Di Marco and his research team discovered a new species of bacteria, Streptomyces peucetius, within a soil sample they obtained from an area near Bari, Italy [10][11]. This new strain of bacteria was produced a compound that was efficacious as a chemotherapeutic agent against many tumors; the compound was later named daunorubicin and is now considered a key intervention administered to patients with AML [12]. Daunorubicin and doxorubicin are part of the class of antibiotics collectively known as the anthracyclines. Anthracyclines can cause cytotoxicity by different mechanisms depending on their intracellular concentration. As reviewed by Gerwitz [13], in vitro studies show there are several possible mechanisms for the anti-tumor effects of these agents including: Inhibition of DNA synthesis, free radical generation leading to either DNA damage or lipid peroxidation, inhibition of DNA topoisomerase resulting in helix super-coiling, DNA alkylation, and DNA cross-linking [13]. The induction of apoptosis was also mentioned as a mechanism of cytotoxicity, but it is likely that apoptosis is a byproduct of the aforementioned cellular stresses, rather than a direct consequence of anthracycline exposure [13]. It is important to note that these mechanisms were observed in vitro, and that in vitro conditions allow for exposure at concentrations that may greatly exceed in vivo concentrations [13]. Pharmacodynamics Although, daunorubicin and doxorubicin are thought to cause cytotoxicity by several different processes, their ability to bind to DNA and prevent DNA replication or transcription is considered to be the primary means of anti-tumor activity in vivo [13][14]. This is because replication is inhibited at anthracycline concentrations that can be reached in vivo following a standard dosage [13]. The two anthracyclines appear to intercalate preferentially to regions of DNA with select base-pair composition, specifically, regions with CGATCG sequences [14]. Rabanni, Finn, Ausio [15] suggest that intercalation stabilizes hydrogen bonds between the two strands of DNA [15]. This means that the energy required to separate the strands is higher, and cannot be achieved by DNA helicase [15]. Thus, strand separation is inhibited, preventing DNA replication and tumor cell proliferation. For both compounds, the chromophore portion (DCBA in fig. 1) of the molecule intercalates between complementary guanine-cytosine (GC)  base pairs on each side of the DNA double-helix (fig. 2). The compound is stabilized in this position by hydrogen bonds on either side of the molecule. The â€Å"D† side of the molecule is held in position with aid from a solvent atom (believed to be ionic sodium), which forms hydrogen bonds between oxygen 4 and 5 to  nitrogen 7 of guanine12 (fig. 2) [14]. The â€Å"A† side of either drug is coordinated by hydrogen bonds from oxygen 9 to nitrogens 2 and 3 of guanine 2 (fig. 2) [14]. As previously mentioned, all of these interactions occur between both daunorubicin/doxorubicin and C/G DNA sequences. However, the added hydroxyl group on C14 of doxorubicin creates an extra association. The hydroxyl appears to shift solvent molecules such that indirect interactions between itself and the phosphate backbone of DNA are created (fig. 3) [14 ]. This added interaction might explain the slightly higher in vitro affinity constant between doxorubicin-DNA (Ka = 1.610-5) as compared to daunorubicin-DNA (Ka = 1.210-5) (in vitro Ka determination performed at 37 °C in 10% fetal calf serum) [17]. Doxorubicin is more potent than daunorubicin. In the case of anthracycline induced inhibition of DNA strand separation, the potency and efficacy are directly related. The increased binding affinity of doxorubicin means that it will associate with DNA and prevent DNA separation at a lower concentration (See supplementary fig.S2). Therefore, pharmacological factors aside, it will be more potent and will prevent tumor cell proliferation at lower concentrations. Synthesis Doxorubicin is a semi-synthetic analog of daunorubicin. The daunorubicin producing bacteria, Streptomyces peucetius, was mutated to the doxorubicin producing subspecies Streptomyces peucetius subsp. caesius [18]. This mutated strain was found to carry an oxidizing cytochrome P450 isoform capable of hydroxylating the C14 of daunorubicin [19]. The gene that encodes this P450 is called doxA [19]. Although, this gene is crucial for doxorubicin production, its presence does not guarantee collectable quantities of doxorubicin (See supplemental figure S.2) [20]. Enzymes, such as dnrH and dnrX, may further oxidize or reduce the newly formed doxorubicin into other metabolites that do not have antitumor abilities [18]. Therefore, in order to make doxorubicin production sustainable, the down regulation of such genes is required to increase doxorubicin yield. Pharmacokinetics Despite their similar molecular structure, daunorubicin and doxorubicin have distinct pharmacokinetic properties. This section will begin by contrasting the differences in elimination, metabolism, and distribution. Bioavailability will not be contrasted because both of these agents are administered intravenously. The section will then conclude with a description of tissue distribution, intracellular distribution, and toxicity. Administration As already mentioned, both anthracyclines are administered via intravenous injection [21][22]. They should not be injected subcutaneously or intramuscularly due to the significant risk of tissue death at and near the injection site [23]. The exact dosage schedule for both daunorubicin and doxorubicin is dependent on several different factors including: age, health, pre-exisiting heart conditions, and renal functioning, therefore exact dosages vary among different patient populations. In terms of daunorubicin, dosage ranges between 30 and 45 mg/m2, whereas doxorubicin dosages range between 40 and 75 mg/m2 during the initial course of treatment [24][25]. Elimination Both compounds are eliminated from the plasma via urinary and biliary mechanisms [23]. However, a much greater proportion of a daunorubicin dose is excreted through the kidneys (14-23%) as compared to doxorubicin (5%), while a larger proportion of doxorubicin was reported to be excreted through the bowels (50%) compared to daunorubicin (40%) [23]. Daunorubicin and doxorubicin are considered to be high clearance drugs. They have a similar clearance value of 1-2 L/Kgà ¯Ã¢â‚¬Å¡Ã… ¸h [26]. The elimination of either drug, along with their metabolites, follows a triphasic decline in plasma concentration [23]. After a 60ml/m2 infusion of daunorubicin/doxorubicin, the plasma concentration/time graph shows that both drugs are eliminated with a similar rate (fig.3) [26]. However the Medsafe ® [23] datasheet for daunorubicin/doxorubicin reports that the plasma T1/2 for the first phase averages 45min daunorubicin and 12min doxorubicin, while the second phase is 18.5hrs daunorubicin, 3.3hrs doxorubicin. Metabolism The primary metabolites of daunorubicin and doxorubicin are daunorubicinol and doxorubicinol respectively. Because of their similar structures, the metabolism of either compound occurs in a likewise fashion. The enzyme most implicated in metabolism is NADPH (nicotinamide-adenine-dinucleotide-phosphate) dependent cytochrome P450 reductase [27]. This enzyme reduces the ketone at C13 to an alcohol to produce daunorubicinol and doxorubicinol [28]. These two products are believed to retain their cytotoxicity and are cleared from the plasma at a similar rate [28][29]. Another common metabolite for either compound is generated via reduction of the glycosidic bond by gycosidases. Glycosidic reduction results in removal of the amino-sugar that is bonded to C7 [28]. This reaction eliminates the anti-tumor capabilities of either compound [28]. Following removal of the amino-sugar, the remaining aglycone is demethylated and then undergoes phase II metabolism (sulfonation or glucuronidation) [23]. Phase II metabolism by sulfonation or glucuronidation increases plasma clearance and enhances elimination. Two other metabolites are listed in literature, 7-deoxydoxorubincolone and 7-deoxydoxorubinone, however the enzyme or enzymes that facilitate these reactions were not noted [30]. Two other enzymes metabolize both daunorubicin and doxorubicin under aerobic conditions, xanthine dehydrogenase and xanthine oxidase, and produce reduced semiquinones and oxygen radicals [31]. These radicals could provide added efficacy to the drug therapy. It has been suggested that advanced stage cancer cells exhibit high oxidative stress and that it may be advantageous to exploit this finding to preferentially and specifically attack and destroy them [30]. Under anaerobic conditions, xanthine dehydrogenase metabolizes doxorubicin to 7- deoxydoxorubicin aglycone, which has been found to be efficacious in the reduction of the drug’s toxicity [31]. Volume of Distribution Daunorubicin and doxorubicin localize in the tissues. The Vd for daunorubicin is 39.2 L/Kg, while the Vd for doxorubicin is 24.6 L/Kg [26]. This indicates that both compounds have high tissue distribution [26]. Although the addition of a hydroxyl group at C14 markedly reduces doxorubicin’s ability to distribute into the tissues (relative to daunorubicin), doxorubicin remains within leukemic cells for a longer duration than daunorubicin (fig. 5) [26]. Upon administration, daunorubicin accumulates within leukemic cells more rapidly than does doxorubicin (fig 5). This is likely because of the increased polar surface area brought on by the added hydroxyl group of doxorubicin, which hinders its ability to cross membranes. However, the added hydroxyl group provides increased binding affinity to DNA [17]. Therefore, it will not leave the cell as rapidly because it will remain bound to DNA [26]. Toxicity The clinical use of doxorubicin and daunorubicin may be limited by their similar inherent toxicity. It goes without saying that chemotherapeutics should not be administered to women who are lactating or pregnant due to significant health complications that can be incurred by the infant or fetus, respectively, therefore these drugs should not be considered in these populations [33]. The use of these agents in a long-term manner is cautioned due to their ability to cause cardiotoxicity [29]. Under aerobic conditions, the semiquinone radical that may be produced during metabolism undergoes redox cycling [27]. Accumulation of reaction oxygen species soon occurs and can cause cytotoxicity [27]. This is believed to account for tissue death in cardiac cells, and is one of the major implications of using the anthracycline class of anti-tumors agents [27]. The cardiotoxicity itself includes effects such as functional damage to mitochrondrial DNA, interference of cytochrome c oxidase, and dysf unctional lipid peroxidation [13]. Personalised Cancer Treatment: Known Markers in Treatment Personalised Cancer Treatment: Known Markers in Treatment Personalised cancer treatment – known markers and what they mean for treatment Contents (Jump to) Known markers and what they mean for treatment Overview Drug target markers Diagnostic and prognostic markers Meta description Keywords Copyscape Known markers and what they mean for treatment Overview Personalised, targeted and hormonal treatments all depend on genetic mutations that can be identified in cancer cells to be effective. These mutations are sometimes referred to as â€Å"markers†. The markers can manifest through over-expression, lack of expression or mutated expression of specific proteins. Some markers can be targeted using specific treatments whereas some can act as measurements for disease diagnosis, prognosis and treatment response. Drug target markers The genes listed below have all been associated in cancer, the majority of which can also be treated. (*) – Targetable genes and proteins that can also be measured to determine treatment response, cancer diagnosis and prognosis. Diagnostic and prognostic markers The following markers are all related to diagnosis, prognosis and treatment progress. Meta description Cancer markers can help with the diagnosis and treatment of cancer and can give access to targeted therapies. Keywords Cancer markers, genetic markers, diagnostic markers, drug target markers Copyscape Checked Sep 2014 CIGNPOST: KNOWN MARKERS AND WHAT THEY MEAN FOR TREATMENT © Cignpost Ltd 2014PAGE | 1 [EB1]If these are genes not proteins then they should be in italics Psychology Christianity: Five Views | Eric L. Johnson Psychology Christianity: Five Views | Eric L. Johnson Review of â€Å"Psychology Christianity- Five Views† by Eric L. Johnson. Title: Psychology Christianity Five Views Author: Eric L. Johnson Publisher: InterVarsity Press. (U.S.A.) 2000 Price:  £14.37 ISBN: 978-0-8308-2848-7 Introduction: In this book review, I intend to cover the following outcomes: evaluate psychological theories against biblical teaching, discuss the contribution psychology has to make to Christian counselling, assess the compatibility of psychology (research and psychotherapy) with Christian counselling and critical examination of psychological theories. About the editor Eric L. Johnson is a teacher, editor, author and director. He attended Toronto Baptist Seminary and proceeded on to Calvin College before going on to Michigan State University where he bagged his PhD. He is an academic psychologist and initially lectured for nine years at the Northwestern College in Minnesota teaching Christian worldview, psychology and theology. Johnson wrote â€Å"Foundations for Soul Care: A Christian Psychology Proposal† and contributed several articles for the Baker Encylopedia of Psychology and Counselling. He argued for the necessity of theology in counselling and psychological research. He is with the Journal of Psychology and Theology as an associate editor. Johnson edited a special issue of the Journal of Psychology and Christianity, entitled â€Å"Psychology within the Christian Tradition† in 1998. He made contributions in two books: â€Å"Christianity and Psychology: Four Views† and â€Å"God under Fire: Modern Scholarship Reinvents God† in addition to editing this book that I am reviewing. Johnson is currently the director of the Society for Christian Psychology and the Lawrence and Charlotte Hoover Professor of Pastoral Care at The Southern Baptist Theological Seminary in Louisville, Kentucky. About the Book Psychology and Christianity: Five Views, is divided into seven chapters and has three hundred and nineteen pages. It is a review and expansion of the first edition titled â€Å"Psychology and Christianity: Four Views†. This book essentially lends to give a precise understanding of human nature and this is an issue that has refused to go. In page 104, we see that Adams argues that the Bible is sufficient to understand human nature and there is nothing psychology can offer but there are opposing arguments. Freud cited in Chapman (2007:41) argues that religion is an illusion. However, Crabb cited in Lutzer (1998:72) argues that we can spoil the Egyptians; take the best of both Christianity and Psychology for our use and become more effective as long as they are not in conflict with the Bible because the Bible will always be superior. The Wesleyan Quadrilateral advocates that four factors (Scripture, Tradition, Experience and Reason) must be considered when reaching decisions. In view of all this on-going debates, Johnson tries in this book to advance the argument for a relationship between Psychology and Christianity, and address the issue of helping Christians to understand and grasp the nettle of psychology. In this edition, there is a fifth view which has been added to the first edition of four views. This fifth view is contributed by John H. Coe and Todd W. Hall and it is titled â€Å"A Transformational Psychology view†. The other four view contributors were still involved in this edition but with revised contributions. The authors put forward five different views of how Psychology and Christianity can be integrated. They are David G. Myers who deals with the levels of explanation; an integration view by Stanton L. Jones, biblical counselling view by David A. Powlison and Christian psychology by Robert C. Roberts co-authored by P.J. Watson. Johnson wrote the opening chapter discussing the history of Christian psychology and also the closing chapter which talks about gaining understanding through the five views put forward by the various authors. The authors gave very good account of themselves in their respective views. Every chapter is concise, well laid out and the thought flow pattern is quite consistent and credible. Content of the book Johnson sandwiches the five views in between two chapters that he authored. He started in this first chapter by looking at the history of Christians in Psychology. In this chapter, Johnson looks at a generic background of psychology but with special reference to how psychology is viewed today. He argues (page 10) that science is a gift from God and that the scientific revolution was initiated by mostly Christians. Some Christians have unreservedly incorporated modern psychology while others like (Bobgan Bobgan 1987) have out-rightly rejected it and called it â€Å"psychoheresy†. Johnson explained in this chapter about the neutrality of this book and that it is rather a picture of the views of the majority of Christians. The second chapter was by David Myers and it deal with levels of explanation. This chapter delves into the subject of human characteristics. This view recognises that Christian theology and Psychology are different and should be treated so but that both should combine well. Myers argues (page 49) that both vary especially in the methodology of research and so each should free to explore as they deem fit. He further argues (page 72-74) that scientific data has enabled him along with some other Christian thinkers to shift from their view of seeing homosexuality as a sin, to understanding the biological explanation of prenatal influences to brain differences especially also considering the fact that the Bible did not have much coverage on the subject matter. Stanton Jones wrote the third chapter which is on the integration view. He shares the same view as Myers; that both Christian theology and Psychology have something to contribute to each other and consequently should be integrated; an aspect that is contrary to Myers view that they should be separated. Christianity is God’s word and psychology is God’s work. Jones argues (page 101) that God’s sovereignty prevails over every facet of human life and that Christian psychologists should benefit from that. However, Jones also shares a common view as Myers with regards to the fact that the Bible does not address some issues adequately (page 101). Jones shares a personal testimony of the tension points that he struggled with in-between Christianity and Psychology. (103-104). Jones became more confused as he desired to be faithful to the Bible, yet, he could not argue with the result that he was actually learning a lot about human nature in Psychology and so through excl usion, he found himself blending both Psychology and Christian theology. The fourth chapter deals with Christian psychology and was co-authored by Roberts and Watson. They argue that understanding God which is revelation (general and special) should be the starting point for the development of psychological theories. These authors (page 155-156) argue that Christian sermons (using Jesus’ sermon on the Mount as an example) are aimed at helping people to live well; dealing with character and transformation of persons and that psychology also deals with how to live, and changing a person’s character with the aim of living well. They identify terminology as the only difference between both. They argue (page 157) that sermon conceptualises psychology. John Coe and Todd Hall co-authored this fifth chapter which deals with the transformational view. They set out, not to develop or defend a model but to shed light on their argument, (page 200) that psychology and Christianity are closely related and that psychology is only an expression of faith and love. This view is the view that has just been added in this edition making it five views. They argue (page 200) in favour of the process and methodology of psychology as a process to new ways of transforming people. This approach looks into the psychologist’s transformation (emotional and spiritual). David Powlison authored the sixth chapter which discusses a Biblical counselling view. He started with a very bold statement â€Å"Christian faith is a psychology†. Also that â€Å"Christian ministry is a therapy† These statements summarises his view. Powlison argues (page 245) that the Scriptures talks about thoughts and intentions of the heart. He further argues that God through the scriptures reveals how human beings should achieve their potentials and a clear change process of attaining such too. Powlison assumes a very new approach in his view; the approach is to delve into the meanings of the word â€Å"psychology† in the very context in which it is used. He argues (page 248) that obviously the meaning is relative. In a bid to drive home his argument, he develops sub themes; Psych 1 – 6. Psych 1 looks at how you work,; Psych 2 looks at the detailed knowledge of human functioning; Pych 3 looks at the competing theories of human personality; Psych 4 de als with the practical application to psychotherapy; Psych 5 looks at a system of professional and institutional arrangements and Psych 6 deals with a mass of ethos. Powlison was really keen on ensuring that his readers have a very clear understanding of his view and goes a step further with a case study as he argues (page 262) that looking at cases is the best way to understand psychological views including biblical counselling. Eric Johnson authored the seventh and closing chapter where he made reference to similar books that has multiple views on the same subject. According to him, this book helps to highlight the point that a group of people, and specifically Christians in this instance, have the same belief but varied perspectives even within the same belief. Johnson (page 293) uses Proverbs 12:15 to affirm that a wise man will be humbled, by that awareness of what he does not know. No one has absolute knowledge except God. He argues that because we are finite creatures, we are limited in terms of views but God is the omniscient observer. He further argues that the more views we are open to, the better our understanding will be, and he encourages his readers especially Christians to dialogue, engage, critique and integrate the strengths of these views as it will enhance their understanding and scope in other to develop their own â€Å"postformal synthesis† (page 309). There is something I found very fascinating about this book. I found out that each chapter have contributing responses from the perspective of the other authors highlighting the strengths and weaknesses of the particular view in light of their own view. My thought. I think that the writing style is easy to read and understand. The chapters are logically laid out and concise and the literary genre is prose. The subsequent contributions from diverse perspectives to each chapter are not common and made it all seem like a conference, answering most questions that readers could have raised. I am the pastor of my local church; I encourage members through prayers, teaching, preaching and pastoral care, based on the Scriptures. I have found myself at crossroads in some contemporary issues which are similar to the observations of Myers and Jones, where they have found the Bible silent on some issues and inadequately addressing some other issues. This is one of my reasons of studying Counselling, and a book like this has opened me up to differing views highlighting both strengths and weaknesses of those views. This review has been an eye opener for me. CONCLUSION In conclusion, I consider the book well-structured as Johnson sets the stage with the historical background and after taking the five views, he borders the book at the end, encouraging scholars to critically and constructively engage to progress the work. Finally, I observe that Johnson claims (page 10) that the book is neutral and that the views represent the collective views of a majority of Christians. This is a very good claim but it would have been very good if he had gone a step further to substantiate his claim with data. However, overall, I consider this book to be of immense value to any Christian psychologists irrespective of their chosen model; it will open them up to differing views even within the Christian community of Psychotherapists. . I identify with Stanton Jones who authored the Integrative view and I will recommend this book to anyone who is seeking a clearer understanding of the integrative model of counselling. References: Chapman, C.N. (2007). Freud, Religion, and Anxiety. USA: Lulu.com. Page 41 Lutzer, E.W. (1998) Pastor to Pastor: Tackling the Problems of Ministry. USA: Kregel Publications. Page 72 Peter Emordi Psychology of Christian Counselling COU2001 1