Reversal of resistance to oxazaphosphorines.
ABSTRACT The oxazaphosphorines including cyclophosphamide (CPA), ifosfamide (IFO) and trofosfamide are one important group of alkylating agents. However, resistance is the major hindrance for success of oxazaphosphorine chemotherapy. The mechanism of resistance to oxazaphosphorines is not fully identified, but recently some novel insights into these aspects have been generated by using sensitive analytical techniques and powerful pharmacogenetic techniques. Potential mechanisms for oxazaphosphorine resistance include decreased activation by cytochrome P450s (e.g. CYP3A4, CYP2C9 and CYP2B6), increased deactivation of the agents by deactivating enzymes such as aldehyde dehydrogenases (ALDHs), increased cellular thiol level, increased DNA repair capacity, and altered cellular apoptotic response to DNA repair, e.g. deficient apoptosis due to lack of cellular mechanisms to result in cell death following DNA damage. In addition, decreased cellular accumulation of cytotoxic species of oxazaphosphorines may also play a role in the resistance. This review highlights the pharmacology of oxazaphosphorine anticancer drugs and possible agents that reverse the resistance to these agents. Possible agents that can overcome oxazaphosphorine resistance include inducers of CYPs, modulators of GSTs and ALDHs, modulators of DNA repair process, antisense oligonucleotides against genes encoding various enzymes and signalling proteins, and novel gene delivery systems. Most of these agents have been investigated in preclinical studies and promising results have been observed. To date, several types of these agents are being evaluated in Phase III trials in cancer patients. Further studies are needed to identify the molecular targets associated with resistance to oxazaphosphorines.
- 01/2012; INFRA-M., ISBN: 978-5-16-005188-8
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ABSTRACT: This review concerns the effects on vision and the eye of medications prescribed at three phases of treatment for women with early-stage breast cancer (BC): (1) adjuvant cytotoxic chemotherapy, (2) adjuvant endocrine therapy, and (3) symptomatic relief. The most common side effects of cytotoxic chemotherapy are epiphora and ocular surface irritation, which can be caused by any of several different regimens. Most notably, the taxane docetaxel can lead to epiphora by inducing canalicular stenosis. The selective-estrogen-receptor-modulator (SERM) tamoxifen, long the gold-standard adjuvant-endocrine-therapy for women with hormone-receptor-positive BC, increases the risk of posterior subcapsular cataract. Tamoxifen also affects the optic nerve head more often than previously thought, apparently by causing subclinical swelling within the first 2 years of use for women older than ~50 years. Tamoxifen retinopathy is rare, but it can cause foveal cystoid spaces that are revealed with spectral-domain optical coherence tomography (OCT) and that may increase the risk for macular holes. Tamoxifen often alters the perceived color of flashed lights detected via short-wavelength-sensitive (SWS) cone response isolated psychophysically; these altered perceptions may reflect a neural-response sluggishness that becomes evident at ~2 years of use. The aromatase inhibitor (AI) anastrozole affects perception similarly, but in an age-dependent manner suggesting that the change of estrogen activity towards lower levels is more important than the low estrogen activity itself. Based on analysis of OCT retinal thickness data, it is likely that anastrozole increases the tractional force between the vitreous and retina. Consequently, AI users, myopic AI users particularly, might be at increased risk for traction-related vision loss. Because bisphosphonates are sometimes prescribed to redress AI-induced bone loss, clinicians should be aware of their potential to cause scleritis and uveitis occasionally. We conclude by suggesting some avenues for future research into the visual and ocular effects of AIs, particularly as relates to assessment of cognitive function.Current eye research 08/2011; 36(10):867-85. · 1.51 Impact Factor
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ABSTRACT: At research of immunosuppressive and acute toxic action of cyclophosphamide pharmacogenetic approach was used – an assessment of results of research of these or those parameters of cyclophosphamide action in mice of genotypes contrast reacting to this preparation. Because of these comparative studies, the set of marker signs defining the final result of cyclophosphamide action was defined: activity of the Cyp2b10, the balance of free sulfhydryl groups in a liver, blood and target cells, and state of reparation systems of DNA damages. Here that fact is essentially new, what not each of the listed markers of cyclophosphamide behavior in an organism separately defines extent of reaction to this preparation, namely their COMBINATION is here decisive. High degree of sensitivity to cyclophosphamide action is defined by a combination of low activity of activation and inactivation systems of a preparation in the metabolism process, the low content of free sulfhydryl groups in target cells and low activity of reparation systems of a DNA damages. The phenotype of resistance to cyclophosphamide action in vivo is defined by the maximum value of these parameters. For the first time is discovered the phenomenon of enhancement cyclophosphamide actions by own active metabolites is revealed, and existence of this phenomenon is proved at research of immunosuppressive, antiproliferative and mutagen action of cyclophosphamide. Important stage in work was research of sensitivity of human peripheral blood lymphocytes to cyclophosphamide and thiophosphamide action. As well as at research of mice of inbred strains, individuals with opposite sensitivity to immunosuppressive action of these alkylating agents and persons with intermediate type of reaction were revealed. In the analysis of the reasons of these differences, it was established that different degree of sensitivity of human peripheral blood lymphocytes could be connected with unequal ability of lymphocytes cytosole to inactivate studied alkylating agents that, in turn, can be caused by intracellular balance of thiol compounds. Results of this stage of work can be used as control indicators when carrying out extracorporeal pharmacotherapy by these preparations as in work limits of normal variability of sensitivity human lymphocytes to cyclophosphamide and thiophosphamide action were defined.01/2010, Degree: Doctor of Sciences, Supervisor: academician L. A. Piruzian., professor V. M. Pisarev