antimetabolites

Summary

Summary: Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033)

Top Publications

  1. Kuriyama K, Honma M, Koyama S, Kim Y. D-cycloserine facilitates procedural learning but not declarative learning in healthy humans: a randomized controlled trial of the effect of D-cycloserine and valproic acid on overnight properties in the performance of non-emotional memory tasks. Neurobiol Learn Mem. 2011;95:505-9 pubmed publisher
  2. Chang C, Maren S. Medial prefrontal cortex activation facilitates re-extinction of fear in rats. Learn Mem. 2011;18:221-5 pubmed publisher
    ..Although neither drug facilitated extinction, they both facilitated the subsequent re-extinction of fear when animals were trained in a drug-free state, suggesting that activating the IL primes behavioral extinction. ..
  3. Lee X, Fox A, SUFRIN J, Henry H, Majcherczyk P, Haas D, et al. Identification of the biosynthetic gene cluster for the Pseudomonas aeruginosa antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid. J Bacteriol. 2010;192:4251-5 pubmed publisher
    ..Overexpression of this cluster in strain PA7, a natural AMB-negative isolate, led to AMB overproduction. ..
  4. Zagorodna O, Martin S, Rutkowski D, Kuwana T, Spitz D, Knudson C. 2-deoxyglucose-induced toxicity is regulated by Bcl-2 family members and is enhanced by antagonizing Bcl-2 in lymphoma cell lines. Oncogene. 2012;31:2738-49 pubmed publisher
    ..Bcl-2 inhibition combined with 2DG may be an effective therapeutic strategy for lymphoma. ..
  5. Lavelle D, Vaitkus K, Ling Y, Ruiz M, Mahfouz R, Ng K, et al. Effects of tetrahydrouridine on pharmacokinetics and pharmacodynamics of oral decitabine. Blood. 2012;119:1240-7 pubmed publisher
    ..Combining oral THU with oral DAC changes DAC pharmacology in a manner that may facilitate accessible noncytotoxic DNMT1-targeted therapy. ..
  6. Montano R, Chung I, Garner K, Parry D, Eastman A. Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA-damaging agents and antimetabolites. Mol Cancer Ther. 2012;11:427-38 pubmed publisher
    ..Delayed administration of SCH900776 may be more effective than concurrent treatment. SCH900776 is currently in phase I clinical trials, and these results provide the rationale and schedule for future clinical trials. ..
  7. Foresti R, Bani Hani M, Motterlini R. Use of carbon monoxide as a therapeutic agent: promises and challenges. Intensive Care Med. 2008;34:649-58 pubmed publisher
  8. Akirav I, Segev A, Motanis H, Maroun M. D-cycloserine into the BLA reverses the impairing effects of exposure to stress on the extinction of contextual fear, but not conditioned taste aversion. Learn Mem. 2009;16:682-6 pubmed publisher
    ..This may suggest that the dysfunctional extinction of fear and taste aversion following exposure to a stressful experience may be modulated by different mechanisms. ..
  9. Hoetzel A, Dolinay T, Vallbracht S, Zhang Y, Kim H, Ifedigbo E, et al. Carbon monoxide protects against ventilator-induced lung injury via PPAR-gamma and inhibition of Egr-1. Am J Respir Crit Care Med. 2008;177:1223-32 pubmed publisher
    ..Mechanical ventilation causes profound lung injury and inflammatory responses. CO treatment conferred protection in this model dependent on PPAR-gamma and inhibition of Egr-1. ..

More Information

Publications62

  1. Zhang X, Sullivan J, Moskal J, Stanton P. A NMDA receptor glycine site partial agonist, GLYX-13, simultaneously enhances LTP and reduces LTD at Schaffer collateral-CA1 synapses in hippocampus. Neuropharmacology. 2008;55:1238-50 pubmed publisher
    ..Our data suggest that GLYX-13 may have unique therapeutic potential as a learning and memory enhancer because of its ability to simultaneously enhance LTP and suppress LTD. ..
  2. Hernlund E, Hjerpe E, Avall Lundqvist E, Shoshan M. Ovarian carcinoma cells with low levels of beta-F1-ATPase are sensitive to combined platinum and 2-deoxy-D-glucose treatment. Mol Cancer Ther. 2009;8:1916-23 pubmed publisher
    ..The findings validate targeting cancer cell glucose metabolism for potentiating platinum chemotherapy in EOC and indicate that reduced beta-F1-ATPase/oxidative phosphorylation distinguishes cells that are amenable to this strategy. ..
  3. Boutros C, Zegdi R, Lila N, Cambillau M, Fornes P, Carpentier A, et al. Carbon monoxide can prevent acute lung injury observed after ischemia reperfusion of the lower extremities. J Surg Res. 2007;143:437-42 pubmed
    ..On the other hand, treatment by bilirubin alone (50 micromol/kg IV) did not modify the extent of pulmonary injury. Exogenous administration of carbon monoxide by inhalation at low doses prevented ALI post-I/R in this model. ..
  4. Yamamoto S, Morinobu S, Fuchikami M, Kurata A, Kozuru T, Yamawaki S. Effects of single prolonged stress and D-cycloserine on contextual fear extinction and hippocampal NMDA receptor expression in a rat model of PTSD. Neuropsychopharmacology. 2008;33:2108-16 pubmed
    ..These findings suggest that DCS, irrespective of its mechanistic involvement in the enhancement of fear extinction, may help to reverse hippocampal plasticity, and thus reverse the NMDA compensatory alterations. ..
  5. Goebel U, Siepe M, Mecklenburg A, Stein P, Roesslein M, Schwer C, et al. Carbon monoxide inhalation reduces pulmonary inflammatory response during cardiopulmonary bypass in pigs. Anesthesiology. 2008;108:1025-36 pubmed publisher
    ..Based on the observations of this study, inhaled carbon monoxide could represent a potential new therapeutic modality for counteracting CPB-induced lung injury. ..
  6. Suliman H, Carraway M, Ali A, Reynolds C, Welty Wolf K, Piantadosi C. The CO/HO system reverses inhibition of mitochondrial biogenesis and prevents murine doxorubicin cardiomyopathy. J Clin Invest. 2007;117:3730-41 pubmed
    ..These findings imply that the therapeutic index of anthracycline cancer chemotherapeutics can be improved by the protection of cardiac mitochondrial biogenesis. ..
  7. van der Westhuyzen R, Hammons J, Meier J, Dahesh S, Moolman W, Pelly S, et al. The antibiotic CJ-15,801 is an antimetabolite that hijacks and then inhibits CoA biosynthesis. Chem Biol. 2012;19:559-71 pubmed publisher
    ..These findings reveal CJ-15,801 as a vitamin biosynthetic pathway antimetabolite with a mechanism similar to that of the sulfonamide antibiotics and highlight CoA biosynthesis as a viable antimicrobial drug target. ..
  8. Portero Tresserra M, Cristóbal Narváez P, Martí Nicolovius M, Guillazo Blanch G, Vale Martínez A. D-cycloserine in prelimbic cortex reverses scopolamine-induced deficits in olfactory memory in rats. PLoS ONE. 2013;8:e70584 pubmed publisher
  9. van der Velden D, Opdam F, Voest E. TAS-102 for Treatment of Advanced Colorectal Cancers That Are No Longer Responding to Other Therapies. Clin Cancer Res. 2016;22:2835-9 pubmed publisher
    ..of action, however, seems to be its incorporation into DNA, which distinguishes TFT from current well-known antimetabolites like 5-fluorouracil (5-FU)...
  10. Natekar A, Pupco A, Bozzo P, Koren G. Safety of azathioprine use during pregnancy. Can Fam Physician. 2011;57:1401-2 pubmed
    ..They are afraid to take a "cancer drug" during pregnancy. What is known about the risks? An increasing body of evidence from prospective cohort studies suggests that azathioprine is safe for the fetus during pregnancy. ..
  11. Naito T. [Optimal immunosuppressive therapy based on pharmacokinetics and pharmacodynamics of antimetabolites in clinical practice]. Yakugaku Zasshi. 2010;130:1695-700 pubmed
    ..The IMPDH activity might be a useful marker reflecting a long-term exposure by MPA. Our findings in this review would contribute to optimal dosing of MMF in immunosuppressive regimen including a calcineurin inhibitor. ..
  12. Zalta A, Dowd S, Rosenfield D, Smits J, Otto M, Simon N, et al. Sleep quality predicts treatment outcome in CBT for social anxiety disorder. Depress Anxiety. 2013;30:1114-20 pubmed publisher
    ..Therapeutic attention to sleep quality prior to initiation of CBT and during the acute treatment phase may be clinically indicated. ..
  13. Myers K, Carlezon W. D-cycloserine effects on extinction of conditioned responses to drug-related cues. Biol Psychiatry. 2012;71:947-55 pubmed publisher
    ..We conclude that it is as yet unclear whether DCS-coupled CET might be a useful approach in the treatment of addiction. ..
  14. Ogawa K, Murasaki T, Sugiura S, Nakanishi M, Shirai T. Organ differences in the impact of p27(kip1) deficiency on carcinogenesis induced by N-methyl-N-nitrosourea. J Appl Toxicol. 2013;33:471-9 pubmed publisher
    ..However, an increased rate of p27-positive cells was not observed in malignant lymphoma of the thymus. These findings suggest that p27 does not control the cell cycle equally in all organs affected by MNU-induced carcinogenesis. ..
  15. Cho G, Kim G, Baek S, Kim H, Kim T, Kim H, et al. Recombinant human erythropoietin reduces aggregation of mutant Cu/Zn-binding superoxide dismutase (SOD1) in NSC-34 cells. Neurosci Lett. 2011;504:107-11 pubmed publisher
    ..Our findings suggest that the anti-oxidant and anti-inflammatory effects of EPO increase the survival of NSC-34/mSOD1 cells and reduce aggregation of the mutant SOD1 protein. ..
  16. Gerhards N, Rottenberg S. New tools for old drugs: Functional genetic screens to optimize current chemotherapy. Drug Resist Updat. 2018;36:30-46 pubmed publisher
    ..For the bulk of cytotoxic therapeutic agents, including DNA-damaging drugs, drugs targeting microtubules or antimetabolites, there are still no reliable biomarkers used in the clinic to predict tumor response...
  17. Alzahrani K, Ali J, Eze A, Looi W, Tagoe D, Creek D, et al. Functional and genetic evidence that nucleoside transport is highly conserved in Leishmania species: Implications for pyrimidine-based chemotherapy. Int J Parasitol Drugs Drug Resist. 2017;7:206-226 pubmed publisher
    ..pyrimidine salvage is replete with opportunities for therapeutic intervention with enzyme inhibitors or antimetabolites. Their uptake into cells depends upon specific transporters; therefore it is essential to establish whether ..
  18. Jabès A, Lavenex P, Amaral D, Lavenex P. Quantitative analysis of postnatal neurogenesis and neuron number in the macaque monkey dentate gyrus. Eur J Neurosci. 2010;31:273-85 pubmed publisher
    ..These data identify an extended developmental period during which neurogenesis might be modulated to significantly impact the structure and function of the dentate gyrus in adulthood. ..
  19. Ducat E, Ray B, Bart G, Umemura Y, Varon J, Ho A, et al. Mu-opioid receptor A118G polymorphism in healthy volunteers affects hypothalamic-pituitary-adrenal axis adrenocorticotropic hormone stress response to metyrapone. Addict Biol. 2013;18:325-31 pubmed publisher
    ..These findings suggest a relatively greater tonic inhibition at hypothalamic-pituitary sites through the mu-opioid receptor and relatively less cyclical glucocorticoid inhibition in subjects with the 118G allele. ..
  20. Hoentjen F, Hanauer S, de Boer N, Rubin D. Two brothers with skewed thiopurine metabolism in ulcerative colitis treated successfully with allopurinol and mercaptopurine dose reduction. Dig Dis Sci. 2012;57:250-3 pubmed publisher
  21. Perez Pozo S, Schold J, Nakagawa T, Sanchez Lozada L, Johnson R, Lillo J. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond). 2010;34:454-61 pubmed publisher
    ..Lowering the uric acid level prevents the increase in mean arterial blood pressure. Excessive intake of fructose may have a role in the current epidemics of obesity and diabetes. ..
  22. Kato M, Kano Y, Sato Y, Shiohara T. Severe Agranulocytosis in Two Patients with Drug-induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms. Acta Derm Venereol. 2016;96:842-3 pubmed publisher
  23. Mo Z, Milivojevic V, Zecevic N. Enforced Pax6 expression rescues alcohol-induced defects of neuronal differentiation in cultures of human cortical progenitor cells. Alcohol Clin Exp Res. 2012;36:1374-84 pubmed publisher
    ..These findings suggest that the effect of alcohol on human neurogenesis is partially due to the reduced expression of transcription factor Pax6 in RG cells. ..
  24. Kumar S, Gupta N, Vivian A. Modern approach to managing vernal keratoconjunctivitis. Curr Allergy Asthma Rep. 2010;10:155-62 pubmed publisher
    ..Consideration also should be given to the patient's specific needs. The basic tenet of treatment is optimal control of symptoms with a minimum of toxic side effects resulting from prolonged use of medication. ..
  25. Seo Mayer P, Thulin G, Zhang L, Alves D, Ardito T, Kashgarian M, et al. Preactivation of AMPK by metformin may ameliorate the epithelial cell damage caused by renal ischemia. Am J Physiol Renal Physiol. 2011;301:F1346-57 pubmed publisher
    ..Furthermore, pretreatment with an AMPK activator before ischemia may attenuate the severity of renal tubular injury in the context of acute kidney injury. ..
  26. Lehman J, Kalaaji A, Rogers R, Stone R. Pemphigoid nodularis: a case report. Cutis. 2011;88:224-6 pubmed
    ..Results of direct immunofluorescence (DIF) testing were negative, which emphasizes the importance of conducting both DIF and IIF when pemphigoid nodularis is suspected. ..
  27. Pirmohamed M. Genetics and the potential for predictive tests in adverse drug reactions. Chem Immunol Allergy. 2012;97:18-31 pubmed publisher
  28. Gaiardi M, Colantoni A, de Luca V, Bartoletti M. D-cycloserine inhibits the development and the expression of locomotor sensitization to amphetamine in rats. Behav Pharmacol. 2010;21:165-70 pubmed publisher
    ..As behavioral sensitization is proposed to model the enhanced 'drug wanting' observed in psychostimulant abusers, the present data suggest that D-cycloserine might be a useful therapeutic approach to its treatment. ..
  29. Ridzlan F, Bahaman A, Khairani Bejo S, Mutalib A. Detection of pathogenic Leptospira from selected environment in Kelantan and Terengganu, Malaysia. Trop Biomed. 2010;27:632-8 pubmed
    ..Pathogenic leptospires can be detected in Malaysian environment and this has the potential to cause an outbreak. Therefore, precautionary steps against leptospirosis should be taken by camp authorities to ensure the safety of trainees...
  30. Garavito M, Narváez Ortiz H, Zimmermann B. Pyrimidine Metabolism: Dynamic and Versatile Pathways in Pathogens and Cellular Development. J Genet Genomics. 2015;42:195-205 pubmed publisher
    ..Next, we discuss the effects of antimetabolites and inhibitors, and finally we consider the consequences of genetic manipulations, such as knock-downs, knock-..
  31. Chen W, Sun Z, Han Z, Jun K, Camus M, Wankhede M, et al. De novo cerebrovascular malformation in the adult mouse after endothelial Alk1 deletion and angiogenic stimulation. Stroke. 2014;45:900-2 pubmed publisher
    ..AVMs were also detected around the ear tag-wound and in other organs. Deletion of Alk1 in EC in adult mice leads to an increased local EC proliferation during brain angiogenesis and de novo brain AVM. ..
  32. Córdoba Cañero D, Dubois E, Ariza R, Doutriaux M, Roldan Arjona T. Arabidopsis uracil DNA glycosylase (UNG) is required for base excision repair of uracil and increases plant sensitivity to 5-fluorouracil. J Biol Chem. 2010;285:7475-83 pubmed publisher
    ..These results suggest that AtUNG excises uracil in vivo but generates toxic AP sites when processing abundant U:A pairs in dTTP-depleted cells. Altogether, our findings point to AtUNG as the major UDG activity in Arabidopsis. ..
  33. Abdelriheem N, Zaki Y, Abdelhamid A. Synthesis of some new pyrazolo[1,5-a]pyrimidine, pyrazolo[5,1-c]triazine, 1,3,4-thiadiazole and pyridine derivatives containing 1,2,3-triazole moiety. Chem Cent J. 2017;11:53 pubmed publisher
    Pyrazolo[1,5-a]pyrimidines are purine analogues. They have beneficial properties as antimetabolites in purine biochemical reactions...
  34. Ganapathy Kanniappan S. Targeting tumor glycolysis by a mitotropic agent. Expert Opin Ther Targets. 2016;20:1-5 pubmed publisher
    ..Yet, successful clinical translation of antimetabolites or energy blockers to treat cancer remains a challenge, primarily due to lack of efficacy and/or systemic ..
  35. Islamian J, Aghaee F, Farajollahi A, Baradaran B, Fazel M. Combined Treatment with 2-Deoxy-D-Glucose and Doxorubicin Enhances the in Vitro Efficiency of Breast Cancer Radiotherapy. Asian Pac J Cancer Prev. 2015;16:8431-8 pubmed
    ..14 and 1.16, respectively. According to the obtained results, the combination treatment may use as an effective targeted treatment of breast cancer either by reducing the single modality treatment side effects. ..
  36. Katircibasi M, Eken A. Gemcitabine-induced coronary vasospasm: A case report. Turk Kardiyol Dern Ars. 2017;45:172-175 pubmed publisher
    ..Coronary ischemia is the most common cardiotoxic effect of gemcitabine, which is due to its antimetabolites. While underlying cause of coronary ischemia following use of gemcitabine is uncertain, endothelial ..
  37. Liu B, Sen H, Nussenblatt R. Susceptibility genes and pharmacogenetics in ocular inflammatory disorders. Ocul Immunol Inflamm. 2012;20:315-23 pubmed publisher
    ..They propose polygenic and composite models of treatment responses to fulfill individualized drug therapy in intraocular inflammatory disorders. ..
  38. Hollo G. Wound healing and glaucoma surgery: modulating the scarring process with conventional antimetabolites and new molecules. Dev Ophthalmol. 2012;50:79-89 pubmed publisher
    ..Both antimetabolites have also been frequently injected before needling revision of failing filtering blebs...
  39. Lodato S, Tomassy G, De Leonibus E, Uzcategui Y, Andolfi G, Armentano M, et al. Loss of COUP-TFI alters the balance between caudal ganglionic eminence- and medial ganglionic eminence-derived cortical interneurons and results in resistance to epilepsy. J Neurosci. 2011;31:4650-62 pubmed publisher
  40. Fukuda W, Takagi T, Katada K, Mizushima K, Okayama T, Yoshida N, et al. Anti-inflammatory effects of carbon monoxide-releasing molecule on trinitrobenzene sulfonic acid-induced colitis in mice. Dig Dis Sci. 2014;59:1142-51 pubmed publisher
    ..These findings indicate that CO released from CORM-3 ameliorates inflammatory responses in the colon of TNBS-challenged mice at least in part through a mechanism that involves the suppression of inflammatory cell recruitment/activation. ..
  41. Firoz B, Henning J, Zarzabal L, Pollock B. Toxic epidermal necrolysis: five years of treatment experience from a burn unit. J Am Acad Dermatol. 2012;67:630-5 pubmed publisher
    ..IVIg did not significantly alter mortality. Although the highest number of cases was due to trimethoprim/sulfamethoxazole, the greatest proportion of deaths was due to allopurinol. ..
  42. Gomes R, Romanek G, Przybycien M, Amaral D, Akahane H. Evaluation of the effect of allopurinol as a protective factor in post ischemia and reperfusion inflammation in Wistar rats. Acta Cir Bras. 2016;31:126-32 pubmed publisher
    ..Allopurinol reduced the concentrations of serum TNF-alpha when used at different times of ischemia followed by reperfusion, which might indicate reduction of the inflammation provoked by the reperfusion injury. ..
  43. Dodmane P, Arnold L, Pennington K, Thomas D, Cohen S. Effect of dietary treatment with dimethylarsinous acid (DMA(III)) on the urinary bladder epithelium of arsenic (+3 oxidation state) methyltransferase (As3mt) knockout and C57BL/6 wild type female mice. Toxicology. 2013;305:130-5 pubmed publisher
    ..However, DMA(V) does not induce hyperplasia in mice, suggesting that urinary concentrations of DMA(III) do not reach cytotoxic levels in DMA(V)-treated mice. ..
  44. Huang T, Chuang H, Chou W, Chen C, Wang H, Chou S, et al. Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality. Nat Neurosci. 2014;17:240-7 pubmed publisher
    ..Our study suggests that TBR1 is important in the regulation of amygdalar axonal connections and cognition. ..
  45. King B, Primeaux S, Zadeh M, de Gruiter J, Plant J, Ferguson A, et al. Olfactory bulbectomy impairs the feeding response to 2-deoxy-D-glucose in rats. Brain Res. 2011;1367:207-12 pubmed publisher
    ..The present results suggest that olfactory input and olfactory neural pathways also mediate, at least in part, the feeding response to a glucoprivic challenge induced by intraperitoneal injection of 2-DG. ..
  46. Radic J, Batinac T, Hadzisejdic I, Nacinović Duletić A, Valković T, Jonjic N. Concurrent basal cell and squamous cell carcinomas associated with hydroxyurea therapy. Acta Dermatovenerol Croat. 2011;19:183-6 pubmed
    ..Therefore, we suggest that in patients on HU therapy with cutaneous side effects, referral to a dermatologist should be obligatory. ..
  47. Zada M, Pattamatta U, White A. Modulation of Fibroblasts in Conjunctival Wound Healing. Ophthalmology. 2018;125:179-192 pubmed publisher
    ..Although anti-inflammatories and antimetabolites have been used with success, these nonspecific agents are not without their complications...
  48. Kurzawski M, Dziewanowski K, Safranow K, Drozdzik M. Polymorphism of genes involved in purine metabolism (XDH, AOX1, MOCOS) in kidney transplant recipients receiving azathioprine. Ther Drug Monit. 2012;34:266-74 pubmed publisher
  49. Thiele W, Krishnan J, Rothley M, Weih D, Plaumann D, Kuch V, et al. VEGFR-3 is expressed on megakaryocyte precursors in the murine bone marrow and plays a regulatory role in megakaryopoiesis. Blood. 2012;120:1899-907 pubmed publisher
    ..Moreover, activation of VEGFR-3 increased platelet counts in thrombopoietin-treated mice significantly and modulated 5-fluorouracil-induced thrombocytosis strongly, suggesting a regulatory role for VEGFR-3 in megakaryopoiesis. ..
  50. Kondo K, Suzukawa K, Sakamoto T, Watanabe K, Kanaya K, Ushio M, et al. Age-related changes in cell dynamics of the postnatal mouse olfactory neuroepithelium: cell proliferation, neuronal differentiation, and cell death. J Comp Neurol. 2010;518:1962-75 pubmed publisher
    ..This observation suggests that the turnover of mature ORNs is slower in the older neuroepithelium compared to the younger neuroepithelium...
  51. Dodd G, Williams S, Luckman S. Functional magnetic resonance imaging and c-Fos mapping in rats following a glucoprivic dose of 2-deoxy-D-glucose. J Neurochem. 2010;113:1123-32 pubmed publisher
    ..This study, therefore, provides further evidence for a common integrated circuit involved in the induction of feeding behaviour, and illustrates the valuable potential of phMRI in investigating central pharmacological actions. ..
  52. Muhammad Kah R, Liang Q, Frost Pineda K, Mendes P, Roethig H, Sarkar M. Factors affecting exposure to nicotine and carbon monoxide in adult cigarette smokers. Regul Toxicol Pharmacol. 2011;61:129-36 pubmed publisher
    ..In conclusion, the models investigated in this analysis, explain about 30-40% of variability in exposure to nicotine and CO. ..
  53. Ucal S, Häkkinen M, Alanne A, Alhonen L, Vepsalainen J, Keinänen T, et al. Controlling of N-alkylpolyamine analogue metabolism by selective deuteration. Biochem J. 2018;475:663-676 pubmed publisher
    ..i>N-alkylated polyamine analogues are polyamine antimetabolites with proven anticancer efficacy...