Reversal of Resistance to Oxazaphosphorines
Department of Pharmacology, Faculty of Medicine, National University of Singapore.Current Cancer Drug Targets (Impact Factor: 3.52). 09/2006; 6(5):385-407. DOI: 10.2174/156800906777723967
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.
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ABSTRACT: The oxazaphosphorines including cyclophosphamide and ifosfamide represent an important group of drugs because of their wide use as antitumor and immuno-modulating agents. This review highlights the effects of polymorphisms of genes involved in the action, distribution, metabolism, and transport of oxazaphosphorines on their pharmacokinetic variability and therapeutic outcomes. Emerging data indicate that polymorphisms of genes encoding cytochrome P450 (CYP) enzymes (CYP3A4, CYP2B6, and CYP2C9), aldehyde dehydrogenases (ALDH1A1, ALDH3A1), glutathione Stransferases (GSTT1, GSTM1, GSTP1), multidrug resistance-associated proteins (ABCC1 and ABCC2), and methylguanine- DNA methyltransferase (MGMT) play an important role in the wide interindividual pharmacokinetic variability and altered clinical outcome of oxazaphosphorine chemotherapy. For example, CYP2B6*5 (C1459T giving rise to an Arg487Cys substitution) and CYP2C19*2 (C430T) are associated with altered response, toxicity, and survival in patients with proliferative lupus nephritis when treated with pulse cyclophosphamide regimens. In paediatric patients with corticosteroid- sensitive nephrotic syndrome, treatment with cyclophosphamide in patients with a GSTM1 null polymorphism gave a significantly higher rate of sustained remission than in patients with the heterozygous or homozygous GSTM1 wildtype. Preliminary preclinical and clinical studies indicate that a number of genetic polimorphisms can affect the disposition and action of oxazaphosphorines, causing large interpatient variability in their pharmacokinetics, response rate and toxicity. A full identification of the role of these genetic polymorphisms would allow the identification of useful and novel strategies to overcome the resistance and toxicity of oxazaphosphorines and to design optimal therapeutic regimens.
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ABSTRACT: Cancer control by radiotherapy (RT) can be improved with concurrent chemotherapy. Outpatient strategies for sarcomas that combine chemotherapy and RT are possible since supportive care and RT techniques have improved. The current status of non-anthracycline chemotherapy in combination with radiation for high-risk sarcoma is reviewed. Ifosfamide with mesna and newer activated ifosfamide agents (ZIO-201 and glufosfamide) have high potential to improve sarcoma cancer control. In Ewing's sarcoma and osteosarcoma, high-dose ifosfamide with mesna (2.8 g/m2/day of each x 5 days; mesna day 6) can be safely given to outpatients using continuous infusion. Reducing ifosfamide nephrotoxicity and central nervous system side effects are discussed. Other outpatient radiosensitization regimens include gemcitabine (600-1000 mg/m2/dose IV over 1 hour weekly x 2-3 doses), temozolomide (75 mg/m2/daily x 3-6 weeks), or temozolomide (100 mg/m2/dose daily x 5) + irinotecan (10 mg/m2/dose daily x 5 x 2 weeks). In osteosarcoma with osteoblastic metastases on bone scan, samarium (1 mCi/kg; day 3 of RT) and gemcitabine (600 mg/m2 IV over 1 hour day 9 of RT) is a radiosensitization strategy. Future drugs for radiosensitization include beta-D-glucose targeted activated ifosfamide (glufosfamide) and sapacitabine, an oral nucleoside with in vitro activity against solid tumors including sarcomas. The potential to treat major causes of sarcoma treatment failure (local recurrence and distant metastases) with concurrent chemotherapy during radiation should be considered in high-grade sarcomas.
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ABSTRACT: Attempts to administer personalized standard cytotoxic chemotherapy based on individual patient characteristics have been disappointing. Alkylating agents are one of the oldest classes of anticancer medicine with a wide variety of molecular actions and thus the potential for broad utility. Bendamustine hydrochloride, a new addition to this class, was previously developed in the 1960s and has now been trialled in hematological malignancies and many solid tumor types as monotherapy or in combination with the known standard of care. It appears to occupy a particular role in resistant or refractory hematological disease and it was approved by the US FDA for the treatment of chronic lymphocytic leukemia in March 2008. Further trials will reveal whether it is likely to become incorporated into front-line regimens in non-Hodgkin's lymphoma and other malignancies.
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