Gene/Protein Disease Symptom Drug Enzyme Compound
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The effectiveness of anti-cancer chemotherapy can be limited by acute suppression of the bone marrow (myelosuppression). There is also a risk of therapy-related secondary haematopoietic malignancy as well as acute and longer term effects in other tissues. Clinical strategies have been established to address some of these problems, particularly toxic effects on the bone marrow (acute myelotoxicity); however, there is still substantial scope for improving the management of chronic toxicity and mutagenicity to haematopoietic cells and collateral damage to non-haematopoietic cells during chemotherapy. In this review, we have discussed a novel strategy that involves the transfer and expression of drug-resistance functions into haematopoietic stem cells and more-mature blood progenitor cells, to overcome both the acute and long-term deleterious effects of anti-tumour treatment in bone marrow. The potential advantages of this approach include: (1) the in vivo selection of protected cell populations, which offers the possibility of intensification or escalation of chemotherapeutic drug doses; (2) a reduction in the frequency of therapy-related leukaemia and (3) tumour sensitisation to chemotherapy at the same time as haematopoietic protection.
Expert Rev Mol Med 1999 Aug 12
PMID:New perspectives for cancer chemotherapy by genetic protection of haematopoietic cells. 1498 53

High-intensity alkylator-based chemotherapy is required to eradicate tumors expressing high levels of O6-methylguanine DNA methyltransferase (MGMT). This treatment, however, can lead to life-threatening myelosuppression. We investigated a gene therapy strategy to protect human granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells (MPB) from a high-intensity alkylator-based regimen. We transduced MPB with an oncoretroviral vector that coexpresses MGMT(P140K) and the enhanced green fluorescent protein (EGFP) (n = 5 donors). At 4 weeks posttransplantation into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, cohorts were not treated or were treated with low- or high-intensity alkylating chemotherapy. In the high-intensity-treated cohort, it was necessary to infuse NOD/SCID bone marrow (BM) to alleviate hematopoietic toxicity. At 8 weeks posttreatment, human CD45+ cells in the BM of mice treated with either regimen were EGFP+ and contained MGMT-specific DNA repair activity. In cohorts receiving low-intensity therapy, both primitive and mature hematopoietic cells were present in the BM. Although B-lymphoid and myeloid cells were resistant to in vivo drug treatment in cohorts that received high-intensity therapy, no human CD34+ cells or B-cell precursors were detected. These data suggest that improved strategies to optimize repair of DNA damage in primitive human hematopoietic cells are needed when using high-intensity anti-cancer therapy.
Mol Ther 2006 May
PMID:In vivo effects of myeloablative alkylator therapy on survival and differentiation of MGMTP140K-transduced human G-CSF-mobilized peripheral blood cells. 1642 96

Determination of minimal criteria, pre-transplantation regimens, and infusion modalities for effective and reproducible bone marrow (BM) therapy in beta-thalassemia is of fundamental importance for clinical application. In this study, using repopulation assays, we first established the minimal proportion of normal BM stem cells that would result in therapeutic benefit in this red blood cell (RBC) disorder. Eight groups of stable chimeric hemizygous beta-thalassemic (hemi-betathal) mice (10-89%) were systematically subjected to cellular, molecular, and patho-physiologic analyses for approximately 2 years. In the chimeric hemi-betathal groups containing 19-24% normal donor cells, all RBC parameters and consequent erythropoiesis were significantly improved. Mice in the 24% chimeric group and above had marked reduction in organ pathology including iron deposits, and survived to a normal lifespan. Altogether, these results established that a range of 19-24% normal BM cells is sufficient for long-term significant correction of the hemi-betathal phenotype. We also determined concomitantly the minimal myelosuppression radiation doses, the number of cells to be infused, and the number of infusions required in order to attain this therapeutic range in hemi-betathal mice. Importantly, with prior minimal myelosuppression with 1 or 2 Gy, and using cell doses of 40 or 60 millions, 100% of the recipients were successfully engrafted at therapeutic levels, provided the cells were administered in two doses. This study has therefore determined the therapeutic chimeric level as 19-24% of normal cells, and has also defined the minimal transplantation modalities necessary for the stable and successful correction of the hemi-betathal phenotype.
Mol Ther 2007 Sep
PMID:Long-term correction of beta-thalassemia with minimal cellular requirement and transplantation modalities. 1751 91

The BAZF (BCL-6b) protein is highly similar to the BCL-6 transcriptional repressor. While BCL-6 has been characterized extensively, relatively little is known about the normal function of BAZF. In order to understand the physiological role of BAZF, we created BAZF-deficient mice. Unlike BCL-6-deficient mice, BAZF-deficient mice are healthy and normal in size. However, BAZF-deficient mice have a hematopoietic progenitor phenotype that is almost identical to that of BCL-6-deficient mice. Compared to wild-type mice, both BAZF-deficient and BCL-6-deficient mice have greatly reduced numbers of cycling hematopoietic progenitor cells (HPC) in the BM and greatly increased numbers of cycling HPC in the spleen. In contrast to HPC from wild-type mice, HPC from BAZF-deficient and BCL-6-deficient mice are resistant to chemokine-induced myelosuppression and do not show a synergistic growth response to granulocyte-macrophage colony-stimulating factor plus stem cell factor. Depletion of CD8 T cells in BAZF-deficient mice reverses several of the hematopoietic defects in these mice. Since both BAZF- and BCL-6-deficient mice have defects in CD8 T-cell differentiation, we hypothesize that both BCL-6 and BAZF regulate HPC homeostasis by an indirect pathway involving CD8 T cells.
Mol Cell Biol 2007 Aug
PMID:Aberrant regulation of hematopoiesis by T cells in BAZF-deficient mice. 1752 24

The bisdioxopiperazines such as (+)-(S)-4,4'-propylenedi-2,6-piperazinedione (dexrazoxane; ICRF-187), 1,2-bis(3,5-dioxopiperazin-1-yl)ethane (ICRF-154), and 4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione (ICRF-193) are agents that inhibit eukaryotic topoisomerase II, whereas their ring-opened hydrolysis products are strong iron chelator. The clinically approved analog ICRF-187 is a pharmacological modulator of topoisomerase II poisons such as etoposide in preclinical animal models. ICRF-187 is also used to protect against anthracycline-induced cardiomyopathy and has recently been approved as an antidote for alleviating tissue damage and necrosis after accidental anthracycline extravasation. This dual modality of bisdioxopiperazines, including ICRF-187, raises the question of whether their pharmacological in vivo effects are mediated through interaction with topoisomerase II or via their intracellular iron chelating activity. In an attempt to distinguish between these possibilities, we here present a transgenic mouse model aimed at identifying the contribution of topoisomerase IIalpha to the effects of bisdioxopiperazines. A tyrosine 165 to serine mutation (Y165S) in topoisomerase IIalpha, demonstrated previously to render the human ortholog of this enzyme highly resistant toward bisdioxopiperazines, was introduced at the TOP2A locus in mouse embryonic stem cells by targeted homologous recombination. These cells were used for the generation of transgenic TOP2A(Y165S/+) mice, which were demonstrated to be resistant toward the general toxicity of both ICRF-187 and ICRF-193. Hematological measurements indicate that this is most likely caused by a decreased ability of these agents to induce myelosuppression in TOP2A(Y165S/+) mice, highlighting the role of topoisomerase IIalpha in this process. The biological and pharmacological implications of these findings are discussed, and areas for further investigations are proposed.
Mol Pharmacol 2007 Oct
PMID:A mouse model for studying the interaction of bisdioxopiperazines with topoisomerase IIalpha in vivo. 1762 80

Myelosuppression and associated immunosuppression are major problems in cancer chemotherapy. Thus, infection remains a significant source of morbidity and mortality during chemotherapy of cancer patients. Viral infections, particularly herpes simplex virus, varicella zoster virus, and cytomegalovirus, result either due to reactivation of latent viruses or new infections as sequelae of chemotherapy and debilitated cell-mediated immunity. Ultimately, the resolution of these infections can only be achieved after the control of malignancy and regaining the patient's ability to mount adequate immune responses. We show here that EM011, a tubulin-binding, nontoxic, orally available anticancer agent, does not alter absolute CD4(+), CD8(+), B220(+), and NK1.1(+) cell counts in immunocompetent mice. More importantly, EM011 treatment at tumor-suppressive dosages (300 mg/kg) does not suppress cell-mediated immune responses in mice experimentally challenged with acute lymphocytic choriomeningitis virus infection, in that mice mount robust virus-specific CD8(+) and CD4(+) T-cell immune responses while maintained on daily drug treatment. Thus, CD8(+) and CD4(+) T-cell expansion and acquisition of effector functions is not perturbed by EM011 treatment. These data provide compelling evidence to support the nonimmunosuppressive nature of EM011 therapy and provide strong impetus for combining chemotherapy with immunotherapy as a novel anticancer strategy.
Mol Cancer Ther 2007 Nov
PMID:Nonimmunosuppressive chemotherapy: EM011-treated mice mount normal T-cell responses to an acute lymphocytic choriomeningitis virus infection. 1802 74

Tissue inhibitors of matrix metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) and are associated with normal and pathologic extracellular matrix turnover. Because the microenvironment is critical for normal hematopoietic stem/progenitor cell function, we aimed to determine whether alterations in the TIMP/MMP balance impact upon normal hematopoiesis in mice. We have used both overexpression and knockout mouse models to determine whether early hematopoiesis is susceptible to potentially pathologic changes in TIMP/MMP level. These studies used TIMP-1(-/-) mice and retroviral vectors co-expressing human TIMP-1 or TIMP-2 linked with the green fluorescent protein (GFP) transduced into bone marrow (BM) cells and transplanted into lethally-irradiated recipient mice. Loss of TIMP-1 in knockout mice or retroviral overexpression of TIMP-1 or TIMP-2 did not alter hematopoietic stem/progenitor function during steady-state hematopoiesis. Surprisingly, even when applying hematopoietic stress through mobilization, chemotaxis, or myelosuppression, murine hematopoiesis was not adversely affected by TIMP-1 or TIMP-2 level. We conclude that TIMP/MMP balance alone does not exert significant influence on blood cell development and homeostasis. An important corollary of these studies is that specific modulation using MMP inhibitors for cancer or immunologic therapy is unlikely to have adverse hematopoietic side effects.
Blood Cells Mol Dis
PMID:Hematopoiesis in mice is extremely resilient to wide variation in TIMP/MMP balance. 1848 63

Dose-limiting toxicity of chemotherapeutic agents, i.e., myelosuppression, can limit their effectiveness. The transfer and expression of drug-resistance genes might decrease the risks associated with acute hematopoietic toxicity. Protection of hematopoietic stem/progenitor cells by transfer of drug-resistance genes provides the possibility of intensification or escalation of antitumor drug doses and consequently an improved therapeutic index. This chapter reviews drug-resistance gene transfer strategies for either myeloprotection or therapeutic gene selection. Selecting candidate drug-resistance gene(s), gene transfer methodology, evaluating the safety and the efficiency of the treatment strategy, relevant in vivo models, and oncoretroviral transduction of human hematopoietic stem/progenitor cells under clinically applicable conditions are described.
Methods Mol Biol 2009
PMID:Chemoprotection by transfer of resistance genes. 1956 27

Methylation of CpG islands in promoter regions is often associated with gene silencing and aberrant DNA methylation occurs in most cancers, leading to the silencing of some tumor suppressor genes. Reversal of this abnormal hypermethylation by DNA methylation inhibitors is effective in reactivating methylation-silenced tumor suppressor genes both in vitro and in vivo. Several DNA methylation inhibitors have been well studied; the most potent among them is 5-aza-2'-deoxycytidine (5-Aza-CdR), which can induce myelosuppression in patients. S110 is a dinucleotide consisting of 5-Aza-CdR followed by a deoxyguanosine, which we previously showed to be effective in vitro as a DNA methylation inhibitor while being less prone to deamination by cytidine deaminase, making it a promising alternative to 5-Aza-CdR. Here, we show that S110 is better tolerated than 5-Aza-CdR in mice and is as effective in vivo in inducing p16 expression, reducing DNA methylation at the p16 promoter region, and retarding tumor growth in human xenograft. We also show that S110 is effective by both i.p. and s.c. deliveries. S110 therefore is a promising new agent that acts similarly to 5-Aza-CdR and has better stability and less toxicity.
Mol Cancer Ther 2010 May
PMID:S110, a 5-Aza-2'-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. 2044 12

The bone marrow microenvironment houses haematopoietic stem cells (HSC), mesenchymal stem cells (MSC) and their progeny, supports haematopoiesis, osteogenesis, osteoclastogenesis, and adipogenesis. It plays a key role in maintaining homeostatic production of erythroid, myeloid or lymphoid cells, appropriate bone mass and bone health throughout life. Through cell-cell adhesion and chemotactic axes, a reciprocal inter-dependent relationship exists between these two cell lineages. Following chemotherapy-induced myelosuppression observed in cancer patients, HSCs are induced to enter into the cell cycle in order to re-establish the damaged microenvironment. These cells not only have the capacity to mobilize to the peripheral blood, but the ability to repopulate the marrow cavity as required. However, depending on the dosage and length of chemotherapy treatment, complications in bone and bone marrow recovery occur. This may manifest as marrow haematopoietic depletion, high marrow fat content, reduced bone formation and aggravated osteoclastic bone resorption. Although the molecular and cellular mechanisms governing injured states of the marrow microenvironment are yet to be fully elucidated, many reports have demonstrated the CXCL12/CXCR4 axis plays an important role in regulating the two cell lineages. Their interaction maintains bone marrow homeostasis and orchestrates its regeneration following chemotherapy. This review explores movement of MSC and HSC, haematopoiesis, commitment of osteoblasts, osteoclasts, and adipocytes, as well as the major signalling pathways that regulate these cellular processes under chemotherapy-treated conditions. This review also discusses molecular targets that are being used clinically or are currently under investigation for preserving the bone marrow microenvironment during or enhancing recovery after chemotherapy.
Curr Mol Med 2010 Jul
PMID:Damage and recovery of the bone marrow microenvironment induced by cancer chemotherapy - potential regulatory role of chemokine CXCL12/receptor CXCR4 signalling. 2054 Jul 6


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