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.
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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.Cancer control: journal of the Moffitt Cancer Center 02/2008; 15(1):38-46. · 2.66 Impact Factor
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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.Future Oncology 06/2008; 4(3):323-32. DOI:10.2217/147966220.127.116.113 · 2.61 Impact Factor
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ABSTRACT: Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.Drug Metabolism Reviews 02/2009; 41(2):89-295. DOI:10.1080/03602530902843483 · 6.29 Impact Factor