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Mechanism of action of demethylating and immune modulatory agents – Introduction
Cancer Treatment Reviews 37 (2011) S1
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Mechanism of action of demethylating and immune modulatory agents – Introduction Introduction For a number of decades, chemotherapy has been the central treatment option for different types of cancer including hematological malignancies. Due to the intensive and continuous work of cooperative clinical study groups, the incremental improvement of combinations of different classical cytotoxic agents has resulted in a clinically relevant increase of patients cured by chemotherapy. On the other hand, a significant portion of patients suffering from cancer diseases have only temporarily benefited from cytotoxic treatment but can not finally be cured by this treatment alone. One of the major issues in improvement of chemotherapy has been the increase of intensity including higher dosages, more stringent application schedules as well as the addition of hematopoietic growth factors to manage hematopoietic toxicity. Furthermore, the concept of autologous stem cell transplantation following highdose chemotherapy had been introduced to further intensify chemotherapy and to manage treatment associated hematoxicity but there are other limitations to further increase chemotherapy dosages. However, during the last years we have learned that – despite all innovation to increase chemotherapy efficacy by dose escalation – there is a limitation for the antitumor effect of cytostatic drugs. Therefore, the search for alternative therapeutic targets has been initiated resulting in the concept of ‘‘targetspecific’’, individualized treatment of patients with solid tumors as well as hematopoietic malignancies. Myelodysplastic syndromes (MDS) are heterogenous diseases which are characterized by ineffective hematopoiesis with an increased risk of evolution to acute myeloid leukemia (AML). Diagnosis of MDS is mainly based on morphological findings and cytogenetics. However, little is known about the underlying pathomechanisms causing MDS. Interestingly, MDS in early stages with relatively slow progression to AML might be a prototype of the multistep concept in leukemogenesis with accumulation of cellular and molecular defects during initiation and disease progression. The model of Knudson postulates ‘two hits’ that are required for the development of cancer, e.g. MDS and consecutive AML. This concept bases on the observation in hereditary cancers, that loss or inactivation of one allele rarely is sufficient to result in the development of tumors or expansion of a malignant clone but loss of the corresponding allele or additional alterations are necessary for the penetrance of clonal cells. A number of mechanisms resulting in silencing of important regulatory genes in hematopoietic cells in MDS/AML have been described during the last two decades including chromosomal deletions (e.g. 5q), DNA mutations (e.g. JAK2, TET2 and others) as well as epigenetic dysregulation such as DNA methylation and histone acetylation. 0305-7372/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2011.04.011
Methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism that is frequently dysregulated in human cancer and plays a critical role in the transcriptional silencing of tumor suppressor genes in cancer. Several fundamental biologic processes can be affected by this epigenetic event in human cancer such as DNA repair, cell cycle control, apoptosis and detoxification. Hypermethylation of CpG islands of genes involved in cell cycle control and apoptosis is a common feature particularly in higher risk MDS. The cyclin dependent kinase inhibitors p15INK4b and p16INK4a are rarely mutated or deleted, but transcription of the p15INK4b gene is often silenced due to abnormal methylation of its promoter region and several studies indicate that roughly 50% of MDS patients show this alteration. Silencing of genes by DNA methylation is a reversible process which is in contrast to the irreversibility of genetic deletions. The introduction of demethylating agents (e.g. 5-azacytidine and 5aza-20 -deoxycytidine) in the treatment of high risk MDS yielded encouraging results by improving hematopoiesis and prolonging survival. Furthermore, the introduction of immune modulatory drugs e.g. Lenalidomide have the potential to significant improve hematopoiesis in well defined molecular subgroups of patients with MDS (deletion 5q) or AML. Therefore, while understanding the mechanism of action of these epigenetic and immune modifying drugs is of interest for the scientific community it also has importance on physicians treating patients with tumor diseases to further optimize and adapt treatment strategies.
Conflict of Interest Both authors received honorarium and travel reimbursement from Celgene. Wolf-K. Hofmann Department of Hematology and Oncology, University Hospital, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany Tel.: +49 621 3834115; fax: +49 621 3834201. E-mail address: [email protected] Carsten Müller-Tidow Department of Hematology and Oncology, University Hospital, Albert-Schweitzer-Straße 33, D-48149 Münster, Germany Tel.: +49 251 8356229; fax: +49 251 8352673 E-mail addresses: [email protected]
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
Mechanism of action of demethylating and immune modulatory agents – Introduction Introduction For a number of decades, chemotherapy has been the central treatment option for different types of cancer including hematological malignancies. Due to the intensive and continuous work of cooperative clinical study groups, the incremental improvement of combinations of different classical cytotoxic agents has resulted in a clinically relevant increase of patients cured by chemotherapy. On the other hand, a significant portion of patients suffering from cancer diseases have only temporarily benefited from cytotoxic treatment but can not finally be cured by this treatment alone. One of the major issues in improvement of chemotherapy has been the increase of intensity including higher dosages, more stringent application schedules as well as the addition of hematopoietic growth factors to manage hematopoietic toxicity. Furthermore, the concept of autologous stem cell transplantation following highdose chemotherapy had been introduced to further intensify chemotherapy and to manage treatment associated hematoxicity but there are other limitations to further increase chemotherapy dosages. However, during the last years we have learned that – despite all innovation to increase chemotherapy efficacy by dose escalation – there is a limitation for the antitumor effect of cytostatic drugs. Therefore, the search for alternative therapeutic targets has been initiated resulting in the concept of ‘‘targetspecific’’, individualized treatment of patients with solid tumors as well as hematopoietic malignancies. Myelodysplastic syndromes (MDS) are heterogenous diseases which are characterized by ineffective hematopoiesis with an increased risk of evolution to acute myeloid leukemia (AML). Diagnosis of MDS is mainly based on morphological findings and cytogenetics. However, little is known about the underlying pathomechanisms causing MDS. Interestingly, MDS in early stages with relatively slow progression to AML might be a prototype of the multistep concept in leukemogenesis with accumulation of cellular and molecular defects during initiation and disease progression. The model of Knudson postulates ‘two hits’ that are required for the development of cancer, e.g. MDS and consecutive AML. This concept bases on the observation in hereditary cancers, that loss or inactivation of one allele rarely is sufficient to result in the development of tumors or expansion of a malignant clone but loss of the corresponding allele or additional alterations are necessary for the penetrance of clonal cells. A number of mechanisms resulting in silencing of important regulatory genes in hematopoietic cells in MDS/AML have been described during the last two decades including chromosomal deletions (e.g. 5q), DNA mutations (e.g. JAK2, TET2 and others) as well as epigenetic dysregulation such as DNA methylation and histone acetylation. 0305-7372/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2011.04.011
Methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism that is frequently dysregulated in human cancer and plays a critical role in the transcriptional silencing of tumor suppressor genes in cancer. Several fundamental biologic processes can be affected by this epigenetic event in human cancer such as DNA repair, cell cycle control, apoptosis and detoxification. Hypermethylation of CpG islands of genes involved in cell cycle control and apoptosis is a common feature particularly in higher risk MDS. The cyclin dependent kinase inhibitors p15INK4b and p16INK4a are rarely mutated or deleted, but transcription of the p15INK4b gene is often silenced due to abnormal methylation of its promoter region and several studies indicate that roughly 50% of MDS patients show this alteration. Silencing of genes by DNA methylation is a reversible process which is in contrast to the irreversibility of genetic deletions. The introduction of demethylating agents (e.g. 5-azacytidine and 5aza-20 -deoxycytidine) in the treatment of high risk MDS yielded encouraging results by improving hematopoiesis and prolonging survival. Furthermore, the introduction of immune modulatory drugs e.g. Lenalidomide have the potential to significant improve hematopoiesis in well defined molecular subgroups of patients with MDS (deletion 5q) or AML. Therefore, while understanding the mechanism of action of these epigenetic and immune modifying drugs is of interest for the scientific community it also has importance on physicians treating patients with tumor diseases to further optimize and adapt treatment strategies.
Conflict of Interest Both authors received honorarium and travel reimbursement from Celgene. Wolf-K. Hofmann Department of Hematology and Oncology, University Hospital, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany Tel.: +49 621 3834115; fax: +49 621 3834201. E-mail address: [email protected] Carsten Müller-Tidow Department of Hematology and Oncology, University Hospital, Albert-Schweitzer-Straße 33, D-48149 Münster, Germany Tel.: +49 251 8356229; fax: +49 251 8352673 E-mail addresses: [email protected]