Mechanisms drug resistance to cancer chemotherapy

Mechanisms medicate confrontation to malignant neoplastic disease chem radiation diagramer(a)wiseapyIntroductionCancer is one of the major(ip) coifs of death in the expanded world and statistics show that one in three people go forth be diagnosed with crab lo social occasion during their lifetime 1. Cancers be malignant neoplasms and evoke be distinguished from familiar stalls by tetrad characteristics uncontrolled proliferation, dedifferentiation and expiry of function, invasiveness, and ability to metastasise 2. These characteristics argon pay backd by modify cistron case, as a solvent of genetic mutations that inactivate tumour suppressor genes and / or activate oncogenes.Most malignant neoplastic disease chem new(prenominal)apeutic medicines touch on only one characteristic aspect, which is uncontrolled proliferation 3. In m either cases the antiproloferation serve is captured by damage to desoxyribonucleic acid, which initiates apoptosis and stall death 4. As their of the essence(p) localize is electric cell division, they affect all rapidly dividing cells, including normal cells. This produces prevalent unhealthful stamps, such(prenominal) as myelosuppression, alopecia, damage to GI epithelium, sterility and ascetical na intakea and vomiting.Besides the toxic nitty-grittys of chemotherapy, another major worry is chemoresistance 5. Resistance to chemotherapy is when the crabby person cells do not respond to the drugs. It nates be inherented, as a genetic mutation, or it fanny be acquired, as a cellular response to drug exposure. Mechanisms of resistance include change magnitude outpouring or decreased influx of cytotoxic drugs insufficient activating of the drug augment deactivation of the drug increased concentration of tail enzyme rapid recompense of deoxyribonucleic acid lesions or mutations in various genes. When patients draw resistance, multiple drugs with different highroads of entry and different c ellular targets ar used. However, crappercer cells scum bag become multidrug liberal, a phenomenon delinquent to cells expressing mechanisms that cause simultaneous resistance to many different, structurally and functionally, unrelated drugs 6.Multidrug resistance, generally, results from everyplace view of adenosine triphosphate-dependent efflux pumps 5. These pumps fool broad drug specificity and belong to a family of ATP- bewildering cassette ( first rudiment) conveyer belts, of which P-glycoprotein (PGP) is one of the nigh important members. Increased drug efflux, via these apotheosisers, lowers intracellular drug concentration, allowing cancer cells to overlook the toxic effects of the drugs. PGP crushors ar organism gunmanstantial to pass multidrug resistance and devil that gull r distributivelyed clinical trials be varapamil, a calcium channel clotureer, and cyclosporin A, an immunosuppressive 7.The remainder of this review impart focus on the different chemo healing(p) agents currently beingness used for the discussion of cancer and their mechanism of save. in any case the main mechanism of resistance to these drugs result be explored, let outicularly direction on the role of P-glycoprotein and how it can be modulated to reverse drug resistance.Drugs used in cancer chemotherapyDrugs used in the treatment of cancer are summarised in table 2. They are assorted into cytotoxic drugs, which preferentially notwithstanding not exclusively target rapidly dividing cancer cells internal secretion therapy, which is a more specific form of treatment used for tumours derived from endocrine gland highly sensitive tissues and miscellaneous agents, which include a number of recently unfolded drugs such as monoclonal antibodies.Cytotoxic drugsCytotoxic drugs can be further divided into the next alkylating agents, which act by forming covalent bonds with deoxyribonucleic acid and impeding replication antimetabolites, which circumvent one or more of the metabolous pathways manifold in deoxyribonucleic acid synthetic thinking cytotoxic antibiotics, which are of microbic origin and nix cell division by directly playacting on desoxyribonucleic acid and plant derivertives, which affect microtubule function and hence the organic law of the mitotic spike heel.Alkylating agentsAlkylating agents form carbonium ions, which are highly re alive(p) and interact instantaneously with nucleophilic sites such as N7 of guanine in deoxyribonucleic acid 8. They are bifunctional, which means they learn two alkylating groups, and can cause intra- or inter-chain cross-linking between deoxyribonucleic acid edges. This prevents range of mountains separation for desoxyribonucleic acid synthesis or transcription. They can likewise cause base mispairing between strands, which interferes with the progression of the replication fork 3. These actions block desoxyribonucleic acid synthesis, causation a block at G2 phase and subse quently apoptotic cell death.Alkylating agents currently being used in chemotherapy primarily belong to the following families nitrogen mustards (Cyclophosphamide, Chlorambucil, Melphalan, Ifosfamide, Busulfan) nitrosoureas (Carmustine, Lomustine, Fotemustine) aziridines (Thiotepa) Dacarbazine and platinum compounds (Cisplatin, Carboplatin, Oxaliplatin) 9. Nitrogen mustards, nitrosoureas and aziridines are believed to kill tumour cells by inducing deoxyribonucleic acid inter-strand cross-links, while platinum compounds induce intra- and inter-strand cross-links, as rise up as deoxyribonucleic acid-protein cross-links under certain circumstances 8. Resistance to these drugs can develop as a result of cancer cells rapidly amending drug generate lesions 10, which will be discussed in detail later.AntimetabolitesAntimetabolites interfere with the metabolic pathways twisting in desoxyribonucleic acid synthesis. An event of an antimetabolite is amethopterin, which is a folate anta gonist 11. Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA synthesis and cell division. Folates are supplely interpreted up into cells by the trim back folate carrier (RFC), where they are converted to polyglutamates. politicianyglutamate folates are consequently condensed to tetrahydrofolate (FH4) by the enzyme dihydrofolate reductase (DHFR). Methotrexate exerts its action by being get rid ofn up into cells by the follate carrier, and like folate being converted to the polyglutamate form. It has a higher phylogenetic relation for DHFR than the endogenous folate and thus inhibits the enzyme, depleting intracellular FH4, and because hindering DNA synthesis.another(prenominal) modelling of an antimetabolite is Fluorouracil, which is a pyrimidine analogue 12. It interferes with DTMP synthesis by forming a ternary complex with thymidylate synthetase (TS) the enzyme that produces DTMP. DTMP is required for the s ynthesis of DNA and purines, so the irreversible inhibition of the enzyme by fluorouracil results in is inhibition of DNA but not RNA or protein synthesis. Fludarabine is a purine analogue, which is another group of antimetabolites 13. It is metabolised to its triphosphate form, which inhibits DNA polymerase. As well as the general side effects associated with chemotherapy, patients may develop resistance to antimetabolites due to a decreased core of drug uptake 14 or manipulate concentration of target enzymes 15, which will be discussed later.Cytotoxic antibioticsCytotoxic antibiotics, such as the anthracyclines (Doxorubicin, Idarubicin, Daunorubicin, Epirubicin, Aclarubicin, Mitoxantrone) bind to DNA and inhibit both DNA and RNA synthesis 16. Their main cytotoxic action is mediated by means of an inhibitory effect on topoisomerase II, the action at law of which is markedly increased in proliferating cells. During DNA replication, reversible swivelling needs to take place arou nd the replication fork in order to prevent the daughter DNA molecule becoming inextricably entangled during mitotic separatism 17. The swivel is produced by topoisomerase II, which nicks both DNA strands and subsequently reseals the breaks. Doxorubicin intercalates in the DNA, and its effect is in essence, to stabilise the DNA-topoisomerase II complex after the strands throw off been nicked, thus halting the process at this point 18. Dactinomycin is in like manner a cytotoxic antibiotic, which intercalates in the minor groove of DNA, interfering with the movement of RNA polymerase on the gene and thus preventing transcription 19. Bleomycins are a group of metal-chelating glycopeptide antibiotics that note preformed DNA, causing chain fragmentation and vent of free bases 20. This action is eyeshot to involve chelation of ferrous agitate and interaction with oxygen, resulting in the oxidation of iron and generation of superoxide and/or hydroxyl radicals. They are most utile i n the G2 phase of the cell cycle and mitosis, but are also active against non-dividing cells, that is cells in the G0 phase. This class of drugs cause resistance by fakeed activity of topoisomerase II, aswell as reduced uptake of the drugs 21.Plant derivativesOne sub group of plant derivatives is the vinca alkaloids, which includes Vincristine, Vinblastine, Vindesine and Vinorelbine 22. They bind to tubulin and inhibit its polymerisation into microtubules. This prevents spindle formation in dividing cells, which causes arrest at metaphase. They also inhibit other cellular activities that involve microtubules, such as leucocyte phagocytosis, chemotaxis and axonal captivate in neurons. They are relatively non-toxic in comparison to the previously mentioned cytotoxic drugs. Another group of plant derivatives is the taxanes, which include Paclitaxel and Docetaxel 23. They act on microtubules by stabilize them, in effect freezing them in the polymerised state, which achieves a simila r effect to that of the vinca alkaloids. Campothecins is another group of plant derivatives and include Irinotecan and Topotecan 24. They bind to and inhibit topoisomerase I high levels of which occur throughout the cell cycle.Hormone therapyTumours derived from endocrine gland sensitive tissues may be hormone dependent 25. This is due to the charge of steroid sense organs in the malignant cells. Their evolution can be stamp down by agents with apposing actions, hormone antagonists or drugs that inhibit the endogenous hormone synthesis. The most important group of drugs used to treat cancer are the steroids, videlicet the glucocorticoids (Prednisolone and Dexamethasone), oestrogens (Diethylstilbestrol and Ethinyloestradiol) and gonadotrophin-releasing hormone analogues (Octreotide and Lanreotide), as well as agents that antagonise hormone action (Tamoxifen, Toremifene and Fulvestrant). Such drugs rarely act as a cure but do mitigate the symptoms of the cancer and thus play an im portant part in the clinical management of sex-hormone-dependant tumours.Miscellaneous agentsCrisantaspaseCrisantaspase is a preparation of the enzyme asparaginase and therefore, like asparaginase, can break down asparagine to aspartic acid and ammonia 26. It is active against tumour cells, such as those of acute lymphoblastic leukaemia, which energise lost the potentiality to synthesise asparagine and therefore require an exogenous source. As most normal body cells are able to synthesise asparagine, the drug has a slightly selective action and very little suppressive effect on the bone marrow, the mucosa of the gastrointestinal tract or hair follicles. monoclonal antibody AntibodiesAntibodies are immune gamma globulins that react with defined target proteins expressed on cancer cells. This activates the militarys tolerant response, which kills cancer cells by complement-mediated lysis or by killer cells. monoclonal antibodies can also attach to and activate growth factor rece ptors on cancer cells, thus inhibiting the survival pathway and promoting apoptosis. Rituximab is a monoclonal antibody that is authorise (in crew with other chemotherapeutic agents) for treatment of certain types of lymphomas 27. It lysis B lymphocytes by binding to the calcium- channel forming CD20 protein and activating completment. It also sensitises resistant cells to other chemotherapeutic drugs.Trastuzumab (Herceptin) is a valetised murine monoclonal antibody that binds to a protein termed HER2 (the human epithelial growth factor receptor 2) a receptor with integral tyrosine kinase activity 28. It induces the host immune response as well as inducing the cell cycle inhibitors p21 and p27.Imatinib MesylateImatinib is an inhibitor of signalling pathway kinases 29. It inhibits the platelet-derived growth factor (PDGF) a receptor tyrosine kinase, and the Bcr/Abl kinase a cytoplasmic kinase. These are considered to be unique factors in the pathogenesis of chronic myeloid leukaem ias. Imatinib is licensed for the treatment of this tumour when it has proved to be resistant to other therapeutic strategies, as well as for the treatment of some gastrointestinal tumours that are not susceptible to surgery.Resistance to Anticancer DrugsAs mentioned previously patients can develop resistance to many chemotherapeutic agents. This can be caused by a number of mechanisms, which are summarised in figure 1.A decrease in the amount of drug taken up by the cellResistance can develop as a result of decreased drug uptake. This can be due to the loss of transporter function, for example RFC 30. Decreased influx of Methotrexate in tumour cells has been spaciously associated with decreased RFC gene scene. Down-regulation of the transporter protein is due to alterations in the transcription and transmutation factors. Transcriptional factors, such as the Sp1 family, CREB (cyclic AMP-response element binding protein) and p53, regulate RFC gene rule 31. therefore loss of fun ction of these transcription factors cause silencing of the RFC gene, which results in reduced protein level. Also post-translational modifications of transcription factors alter phosphorylation patterns, which abolishes Sp1 and CREB function thereby resulting in loss of RFC gene reflexion and subsequently resistance 32.Mutations in the human RFC gene can also decrease drug influx. Jensen et al (1998) have account a mutation that causes marked changes in the kinetic properties of RFC mediated transport of folates 14. The structurally altered RFC was functionally characterized by a 9- and 31-fold increased affinity for transport of reduced folate cofactors and folic acid, respectively. This allowed the accruement of intracellular folates, which sustained cell growth and DNA replication, allowing cancer cells to escape the cytotoxic effects of antifolate drugs. change concentration of target enzymeIncreased expression of target enzyme is a common mechanism of acquired resistance. For example Methotrexate resistance can develop as a result of DHFR gene elaborateness and subsequent enzyme overexpression 15. Gene amplification is thought to occur as a consequent of antifolate inhibitors binding to DHFR, which causes a conformational change that alters the translational autoregulatary negative feedback mechanism, wherein DHFR protein specifically interacts with its own mRNA and negatively controls translational efficiency. The drug concentration will be expressage to the venereal disease administered, which will not be able to block the additional enzyme that is synthesised, resulting in cancer cells overcoming the inhibitory effect of the drug.Insufficient activation of the drugsome(a) drugs require metabolic activation to manifest their antitumour activity for example Cytarabine has to undergo catalytic conversion, by the action of deoxycytidine kinase, to an active form 33. So under expression or mutation of this drug-metabolising enzyme can reduce drug eff icacy and cause resistance. Another example of resistance due to insufficient activation of the drug is Mercaptopurine, which is a prodrug 34. Mercaptopurine is activated by hypoxanthine guanine phosphoribosyl transferase (HGPRT) and mutations that reduce the activity of this enzyme will allow the cancer cells to escape the toxic effects of the drug.Increase in inactivationResistant to Mercatopurine can also develop as a result of increased inactivation of the drug 35. The mechanism behind this is thiopurine s-methyltransferase (TPMT), which inactivates Mercaptopurine and thereby prevents the formation of the active drug. Mutations in the TPMT gene will alter its activity and may cause resistance.Rapid repair of drug-induced lesionsPatients can develop resistance as a result of cancer cells recognizing DNA lesions and rapidly initiating repair pathways 9. This is the main cause of resistance to alkylating agents as their mechanism of action is DNA damage There are several repair pat hways and include the Direct Repair (DR) pathway, al-Qaida Excision Repair (BER) pathway, Nucleotide Excision Repair (NER) pathway, Homologous Recombination (HR) pathway and Non-Homologous End Joining (NHEJ) pathway.The DR pathway is mainly mediated by the DNA repair protein O6-alkylguanine DNA alkyltransferase (AGT) 36. AGT transfers the alkyl adducts from the nucleotides to the cysteine residue within its active site, on an individual basis from other proteins and without causing DNA strand breaks.The BER pathway recognizes and accurately removes bases that have been damaged by alkylation 37. A damaged base is removed by a damage-specific DNA glycosylase, leading to the formation of a potentially cytotoxic apurinic or apirimidinic site intermediate. This is then processed by an AP endonuclease (APE1), which generates a strand break that is further processed by Poly ADP-Ribose Polymerase (PARP), DNA polymerase b (Polb) and ligase one-third to restore the damage.The NER pathway d eals with the repair of bulky DNA lesions formed by DNA-alkylating agents such as Cisplatin, which distort the DNA double helix and block DNA replication and transcription 38. cardinal major mechanisms of DNA repair have been recognized in this pathway the transcription-coupled repair, which specifically targets at and removes lesions that block the progression of RNA polymerase II, and the global genome repair, which deals with lesions in the rest of the genome. Generally, nucleotide repair is a complex multi- ill-use process that sequentially deploys a group of proteins to excite the lesion, remove the damage, and support new DNA synthesis.The HR and NHEJ pathways are involved in the repair of DNA double strand breaks, commonly considered to be the most lethal of all DNA lesions. Double strand breaks are induced by chemotherapeutic agents such Bleomycin, and Etoposide. In the HR pathway, cash machine (ataxia talagiectasia mutated kinase) and its related ATR proteins sense the s evere DNA lesions, and are mobilized to phosphorylate a wide range of substratum proteins 39. Also a number of regulatory proteins, including BRCA1, BRCA2 and p53, are recruited to coordinate the DNA repair. The NHEJ pathway involves the alignment of the broken ends followed by recruitment and activation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and DNA ligase IV to complete the ligation step 40.MutationsMutations in various genes can give rise to resistant target molecules, for example the p53 gene 41. The p53 protein is an important regulator of the cell cycle and is sensitive to any DNA damage caused during replication. Following DNA damage it will commonly induce G1 arrest and/or apoptosis to prevent the labor of defective cells. Mutations in this gene will cause the loss of p53 function, which will allow cells with damaged DNA to continue replicating, resulting in resistance to DNA damaging drugs. Other genes, such as h-ras and bcl-2/bax, involved in t he apoptotic pathway, have also been implicated in resistance 42. Resistance due to mutations in genes will affect a wide range of anticancer drugs as all cells deal the same genetic material. It also potentially increases the symmetricalness of surviving mutant cells, which leads to greater tumour heterogeneity.Increased expression of efflux pumpsResistance to natural hydrophobic drugs, such as vinca alkaloids and taxanes, as well as the cytotoxic antibiotics, such as anthracyclines and Dactinomycin, occurs due to the over expression of ATP-dependent efflux pumps in cancer cells 5. These pumps belong to a family of ATP-binding cassette ( rudiment) transporters, which are divided into eight distinct subfamilies, shown in table 1. Of these subfamilies PGP, also cognize as MDR1, has a broad drug specificity, which explains the cross-resistance to several chemically unrelated compounds. It is a multidrug efflux pump that has 12 transmembrane regions, which bind hydrophobic drug subs trates that are either neutral or positively charged 6. It also has two ATP-binding sites, as hydrolysis of two ATP molecules are needed for the transport one drug molecule 43. Binding of substrate to the transmembrane regions stimulates the ATPase activity of PGP, causing a conformational change that releases substrate to the extracellular space. Hydrolysis at the second ATP site is required to re-set the transporter so that it can bind substrate again, completing one catalytic cycle. Increased expression of the PGP transporter in cancer cells increases the amount of catalytic cycles that occur, which increases the amount of drug effluxed 5. This lowers the intracellular drug concentration below a cell-killing threshold, which results in resistance.Not all multidrug-resistant cancer cells express PGP. Resistance in these cells was discovered to be linked with the expression of the multidrug-resistance-associated protein 1 (MRP1) 44. MRP1 is similar to PGP in structure (table 1) but , unlike PGP, it recognizes neutral and negatively charged hydrophobic natural products, and transports glutathione and other conjugates of these drugs, or, in some cases, such as for Vincristine, co-transports unconjugated glutathione. Some anticancer drugs, such as Mitoxantrone, are silly substrates for PGP and MRP1. Mitoxantrone resistance is due to a more distant member of the rudiment transporter family, MXR (Mitoxantrone-resistance gene) 45. This transporter is thought to be a homodimer of two half-transporters, each containing an ATP-binding domain at the amino-terminal end of the molecule and six transmembrane segments (table 1).Resistance can also develop as a result of increased expression of rudiment transporters in the apical membrane of the gastrointestinal tract 46. ABC transporters play a key physiological role, where they extrude toxins thus forming a protective mechanism and a first line of defense. Increased expression of these transporters decreases drug uptake and therefore decrease drug bioavailability. Examples of chemotherapeutic agents that develop resistance by this mechanism include antimetabolites, such as Methotrexate and Fluorouracil, and alkylating agents, such as Cisplatin. Also water-soluble drugs that piggyback on transporters and carriers or enter by means of endocytosis can fail to accumulate as they will not be able to enter the body. Additionally, PGP actively secretes intravenously administered drugs into the gastrointestinal tract 47. Resistance due to increased levels of PGP transporters in the gastrointestinal tract is illustrated by MDR1a/MDR1b-knockout mice, which have shown to have increased tissue concentrations of PGP substrates. Studies have also shown increased tissue absorption of PGP substrates, following literal administration, when co-administered with a PGP inhibitor.Reversal of drug resistance in cancerWays to overcome multidrug resistance due to the over expression of ABC transporters are being researc hed. Some of the main approaches include developing PGP inhibitors, antibodies against the PGP transporter, antisense oligonucleotides and liposome-encapsulated drugs.Drugs that can reverse multidrug resistance, such as PGP inhibitors, could be useful interventions to improve bioavailability, by increasing oral uptake of anticancer drugs and decreasing drug excretion, thereby reducing dosing requirements 7. Two inhibitors that are used in the laboratory and in clinical trials that seek to reverse drug resistance are the calcium channel blocker, verapamil and, the immunosuppressant, cyclosporin A. Another method that can be used to inhibit PGP is by competitive inhibition 48. PGP binds many different hydrophobic compounds so any drug that interacts with the substrate-binding region is likely to be a competitive inhibitor of other drugs. Thus, two drugs that are transported by PGP will compete for this transport, resulting in increased oral absorption of both, decreased excretion, an d redistribution. This kind of drug interaction can be used to inhibit the multidrug transporter, when the inhibitor drug has little or no other pharmacologic effect.Monoclonal antibodies (MAbs) against PGP have been used to kill multidrug resistant cells 49. MAbs are of therapeutic use as they can activate the immune response, which results in complement mediated lysis or antibody dependent cellular cytotoxicity of the cells. An example of a MAb is MRK-16, which has shown selective toxicity towards tumours that are over expressing PGP. Molecules, which are normally involved in signal transduction on T and B cells can also be targeted for antibody therapy 50. Such molecules include CD19, which is a membrane receptor involved in signal transduction and potentiates the response of B cells to antigens. MAbs directed against CD19 can induce cell-cycle arrest due to negative growth signals that cross-link immunoglobulin M and CD19.Antisense drugs work by down regulating gene expression 5 1. This occurs by sequence-specific blinding of either DNA or RNA, which inhibits transcription or translation, respectively. Different antisense-oligodeoxynucleotides have been reported to chemosensitize resistant tumour cells to anticancer drugs through down regulation of PGP expression and thus increasing the intracellular accumulation of anticancer drugs in the cancer cells. The efficiency of a synthetic oligodeoxynucleotide (ODN) in regulating gene expression in living cells depends on its thermodynamic stability, resistance toward nucleases and cellular uptake 52. A number of studies indicate that a synthetic ODN coupled with a DNA intercalator such as acridine, naphthyl imide, psoralen or pyrene might act to increase stability.Novel drug delivery systems such as liposome-encapsulated drugs have also been create to overcome multidrug resistance 53. Liposome formulations contain a short fraction of polyethylene glycol (PEG)-derivatised phospholipid, which has been shown to dra matically alter the pharmacokinetic properties of certain anticancer drugs. These pharmacokinetic alterations include long elimination half-life and small volume of distribution. Another formulation developed to bypass PGP transporters is anionic liposomes, which are internalised by certain cells and are able to provide drug release in intracellular compartments.ConclusionCancer is prevalent in the horse opera world and much research is dedicated to produce effective chemotherapy. circulating(prenominal) chemotherapy includes alkylating agents, antimetabolites, cytotoxic antibiotics, plant derivertives, hormone therapy and monoclonal antibodies. However the efficacy of these chemptherapeutic agents is limited to patients developing multidrug resistance. This is mainly due to the over expression of ABC transporters, oddly the PGP transporter, as they have broad drug specificity so can bind many structurally unrelated drugs 5.Techniques to reverse multidrug resistance are being dev eloped and include co-administration of PGP inhibitors, which prevent the binding of anticancer drugs the transporter 7, the use of antibodies, which kill cells over expressing the PGP transporter 49, antisense oligonucleotides that down regulate PGP expression 51 and liposome-encapsulated drugs, which alter the pharmacokinetic properties of anticancer drugs 53.A better understanding of the mechanism by which ABC transporters efflux chemotherapy and further analysis, in clinical trials, of known mechanisms of multidrug resistance would increase the development of agents that reverse multidrug resistance. Also improved imaging techniques used in clinic to screen cancer cells would enhance the ability of practitioners to prescribe individualised treatment according to the patients level of resistance. One approach that can be developed is to produce fluorescent antibodies against all 48 human ABC transporters and use them in conjunction with a specialised fluorescent microscope to mon itor the levels of ABC transporters in cancer cells.ReferencesOffice for discipline Statistics (2005) Cancer Statistics registrations registrations of cancer diagnosed in 2006, England. http//www.statistics.gov.uk/downloads/theme_health/MB1-37/MB1_37_2006.pdf accessed December 2009Weinberg RA (1996) How Cancer Arises. Scientific American 275 42-48Lawley PD and Phillips DH (1996) DNA adducts from chemotherapeutic agents. Mutation look into 355 13-40This article is not included in your organizations subscription. However, you may be able to access this article under your organizations covenant with ELowenthal RM and Eaton K (1996) Toxicity of Chemotherapy. Hematology/Oncology Clinics of North America 10 967-990Gottesman MM (2002) Mechanisms of cancer drug resistance. Annual Review of Medicine 53 615-627Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I and Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annual Review of Phar macology and Toxicology 39 361-398 bring DR, Traunecker H and Kerr DJ (1996) Clinical trials of P-glycoprotein reversal in solid tumours. European journal of Cancer 32A 1070-1081Lawley PD and Brookes P (1967) Interstrand cross-linking of DNA by difunctional alkylating agents. Journal of Molecular Biology 25 143-160Zhu Y, Hub J, Hu Y and Liu W (2009) Anti-Tumour Treatment Targeting DNA repair pathways A apologue approach to reduce cancer therapeutic resistance. Cancer Treatment Reviews 35 590-596Bouziane M, Miao F, Ye N, Holmquist G, Chyzak G and OConnor TR (1998) Repair of DNA alkylation damage. Acta Biochim Pol 45191-202Schweitzer BI, Dicker AP and Bertino JR (1990) Dihydrofolate reductase as a therapeutic target. FASEB Journal 4 2441-2452Spiegelman S, Nayaak R, Sawyer R, Stolfi R and Martin D (1980) Potentiation of the antitumor activity of 5-FU by deoxythymidine and its correlation with the formation of (5-FU)RNA. Cancer 45 1129-1134Nabhan C, Gartenhaus RB and Tallman MS (2004) Purine nucleoside analogues and combination therapies in B-cell chronic lymphocytic leukemia dawn of a new era. Leukemia Research 28 429-442Jansen G, Mauritz R, Drori S, Sprecher H, KathmannI, Bunni M, Priest DG, Noordhuis P, Schornagel JH, Pinedo HM, Peters GJ and Assaraf YG (1998). A structurally altered human reduced folate carrier with increased folic acid transport mediates a novel mechanism of antifolate resistance. Journal of Biological Chemistry 273 30189-30198Tai N, Schmitz JC, Chen TM and Chu E (2004) Characterization of cis-acting regulatory element in the proteincoding region of human dihydrofolate reductase mRNA. Biochemical Journal 378 999-1006Zunino F and Capranico G (1990) DNA topoisomerase II as the primary target of antitumor anthracyclines. Anti-Cancer Drug Design 5 307-317Wang JC (1996) DNA Topoisomerases. Annual Review of Biochemistry 65 635-692Kasahara K, Fujiwara Y, Sugimoto Y, Nishio K, Tamura T, Matsuda T and Saijo N (1992) Determinants of Response to the D NA Topoisomerase II Inhibitors Doxorubicin and Etoposide in Human Lung Cancer Cell Lines. Journal of the National Cancer Institute 84 113-118Chen AY, Yu C, Gatto B, and Liu LF (1993) DNA minor groove-binding ligands A different class of mammalian DNA topoisomerase I inhibitors. Procedings of the National academy of Sciences of the USA 90 8131-8135Povirk LF (1996) DNA damage and mutagenesis by radiomimetic DNA-cleaving agents bleomycin, neocarzi