Target Validation Information
TTD ID	T34743
Target Name	Bacterial Penicillin binding protein (Bact PBP)
Type of Target	Successful
Drug Potency against Target	Adenine	Drug Info	IC50 = 18 nM	[26]
	Amoxicillin	Drug Info	IC50 = 30 ng/mL	[5]
	Ampicillin	Drug Info	MIC50 = 0.25 ug/ml	[10]
	Azlocillin	Drug Info	IC50 = 100 ng/mL	[42]
	Bleomycin	Drug Info	IC50 = 38.4 nM	[3]
	Cefadroxil	Drug Info	IC50 = 3000 nM	[48]
	Cefamandole	Drug Info	IC50 = 4110 nM	[30]
	Cefazolin	Drug Info	IC50 = 100 ng/mL	[18]
	Cefonicid	Drug Info	IC50 = 6800000 nM	[27]
	Cefoperazone	Drug Info	IC50 = 190000 ng/mL	[50]
	Cefotetan	Drug Info	IC50 = 8000000 ng/mL	[46]
	Cefoxitin	Drug Info	IC50 = 185 ng/mL	[18]
	Ceftazidime	Drug Info	MIC50 = 64 ug/ml	[10]
	Cefuroxime	Drug Info	IC50 = 105 ng/mL	[47]
	Cephapirin	Drug Info	IC50 = 8900 nM	[33]
	Clofazimine	Drug Info	IC50 = 22 nM	[29]
	Cyclacillin	Drug Info	IC50 = 42000 nM	[48]
	Cyclophosphamide	Drug Info	Ki = 2.3 nM	[2]
	Dacarbazine	Drug Info	IC50 = 10000 ng/mL	[45]
	Dactinomycin	Drug Info	IC50 = 7900 nM	[12]
	Daunorubicin	Drug Info	IC50 = 500 nM	[40]
	Dicloxacillin	Drug Info	IC50 = 220 ng/mL	[41]
	Flucloxacillin	Drug Info	IC50 = 180 ng/mL	[41]
	Idoxuridine	Drug Info	IC50 = 4300 nM	[14]
	Ifosfamide	Drug Info	IC50 = 6.2 nM/mL	[28]
	Lomustine	Drug Info	IC50 = 52600 nM	[43]
	Mechlorethamine	Drug Info	IC50 = 1161000 nM	[49]
	Mercaptopurine	Drug Info	IC50 = 149.5 nM	[11]
	Methoxsalen	Drug Info	IC50 = 2900 nM	[20]
	Meticillin	Drug Info	IC50 = 90 ng/mL	[9]
	Nelarabine	Drug Info	IC50 = 800 nM
	Oxacillin	Drug Info	IC50 = 2000 ng/mL	[5]
	Penicillin	Drug Info	MIC50 = 0.06 ug/ml	[10]
	Penicillin V	Drug Info	IC50 = 100 ng/mL	[42]
	Piperacillin	Drug Info	IC50 = 2 nM
	Primaquine	Drug Info	Ki = 220 nM	[7]
	Proflavine	Drug Info	IC50 = 1533 nM	[51]
	Streptozocin	Drug Info	IC50 = 30000 nM	[34]
	Uracil mustard	Drug Info	IC50 = 5100 nM
Action against Disease Model	Ampicillin	Drug Info	RWJ-54428 (MC-02,479) is a new cephalosporin active against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The potency of this new cephalosporin against MRSA is related to a high affinity for penicillin-binding protein 2a (PBP 2a), as assessed in a competition assay using biotinylated ampicillin as the reporter molecule. RWJ-54428 had high activity against MRSA strains COL and 67-0 (MIC of 1 micro g/ml) and also showed affinity for PBP 2a, with a 50% inhibitory concentration (IC(50)) of 0.7 micro g/ml. RWJ-54428 also displayed excellent affinity for PBP 5 from Enterococcus hirae R40, with an IC(50) of 0.8 micro g/ml and a MIC of 0.5 micro g/ml. The affinity of RWJ-54428 for PBPs of beta-lactam-susceptible S. aureus (MSSA), enterococci (E. hirae), and Streptococcus pne uMoniae showed that the good affinity of RWJ-54428 for MRSA PBP 2a and E. hirae PBP 5 does not compromise its binding to susceptible PBPs. RWJ-54428 showed stability to hydrolysis by purified type A beta-lactamase isolated from S. aureus PC1. In addition, RWJ-54428 displayed low MICs against strains of S. aureus bearing the four classes of staphylococcal beta-lactamases, including beta-lactamase hyperproducers. The frequency of isolation of resistant mutants to RWJ-54428 from MRSA strains was very low. In s uMmary, RWJ-54428 has high affinity to multiple PBPs and is stable to beta-lactamase, properties that may explain our inability to find resistance by standard methods. These data are consistent with its excellent activity against beta-lactam-resistant gram-positive	[1]
	Balofloxacin	Drug Info	MIC on Mycobacteri uM tuberculosis MTB 09710 clinical isolate: 16000 ng/mL	[36]
	Busulfan	Drug Info	The results obtained by Huntingdon Research Centre participating in a blind trial of the micromass assay for the prediction of teratogenic potential are presented. Twenty-five coded compounds were tested without S-9 mix using a pre-agreed protocol; three compounds were later tested with S-9. The data were assessed for sensitivity, specificity and accuracy using three separate sets of criteria based on either concentration (the <500 m ug/ml rule (i) and the <50 m ug/ml rule (ii)) or specific inhibition of cell differentiation at relatively non-cytotoxic concentrations (the 2-fold rule (iii)). The best in vivo/in vitro correlation was obtained using the 2-fold rule; the <500 m ug/ml rule was the most sensitive but gave a high false positive rate and the <50 m ug/ml rule was of low overall accuracy (60%). It is suggested that selective inhibition of differentiation of one cell type and cytotoxicity at low dose levels may also indicate risk of embryo-foeto toxicity, a factor to be considered with the pharmacokinetics of the compound. The teratogens procarbazine, methotrexate and caffeine were not detected; diphenhydramine and furazolidone initially classified as non-teratogens in vivo, were predicted as teratogens by the micromass assay.	[37]
	Carbenicillin	Drug Info	Reduced cell permeability and target penicillin-binding protein modification were investigated as mechanisms of intrinsic resistance in strains of Pseudomonas aeruginosa resistant to carbenicillin (MIC greater than 128 mg/L) independently of beta-lactamase production. The carbenicillin-resistant strains were also remarkably resistant to other beta-lactams, quinolones, tetracyline and chloramphenicol, whereas carbenicillin-hypersusceptible strains (MIC less than 2 mg/L) were very sensitive to these antimicrobial compounds. These observations suggested a non-specific mechanism of resistance involving reduced permeability of the outer layers of the bacterial cell. However, carbenicillin-resistant and carbenicillin-sensitive strains had identical porin levels and the target penicillin-binding proteins of carbenicillin-resistant (MIC 256-2048 mg/L), carbenicillin-sensitive (MIC 64 mg/L) and carbenicillin-hypersusceptible (MIC 0.015 mg/L) strains were equally sensitiveto beta-lactams. Thus, subtle changes in porin function or additional outer-membrane barriers regulating permeability may be involved in intrinsic resistance.	[44]
	Carboplatin	Drug Info	Cisplatin and carboplatin were used to treat four leukemic cell lines (CEM, HL60, K562 and U937), blast cells from 10 leukemic patients and hematopoietic progenitors from five uMbilical cord blood samples.The mean IC50 of leukemic cell lines was 0.4 and 6.2 microg/ml, the mean IC50 of patients' leukemic blasts was 2.0 and 22.4 microg/ml and the mean IC50 of hematopoietic progenitors (BFU-E, CFU-E and CFU-GM) was 1.8 and 1.7 microg/ml for cisplatin and carboplatin, respectively.	[8]
	Cefdinir	Drug Info	Ritipenem is highly bacteriolytic against Haemophilus influenzae. Bacterial lysis was shown after treatments with ritipenem and cefsulodin at their MICs and after treatments with fropenem and cefdinir at four times their MICs, indicated by decreases in the culture turbidities and by morphological changes of the destroyed cells. These beta-lactams were preferentially bound topenicillin-binding protein (PBP) 1b. Ritipenem, fropenem, and cefsulodin exhibited poor affinities to PBPs 3a and 3b, but cefdinir showed high affinities to these PBPs. Microscopic examinations revealed that selective PBP 3 inhibitors, such as aztreonam and cefotaxime, inhibited lysis induced by ritipenem. These results suggest that the preferential inactivation of PBP 1b could be essential to induce the lysis of H. influenzae cells and that binding to PBPs 3a and 3b may interfere with lysis.	[4]
	Cefepime	Drug Info	MIC on Penicillin-Binding Proteins of Escherichia coli MC4100 strain: 15 ng/mL	[22]
	Cefixime	Drug Info	The antimicrobial activities of cefixime, cefpodoxime, and ceftibuten were determined with 18 ampicillin-susceptible (Amps), 13 ampicillin-resistant beta-lactamase-producing (AmprBLP), and 7 ampicillin-resistant non-beta-lactamase-producing (AmprNBLP) strains of Haemophilus influenzae. An effect of inocul uM density on apparent MIC, the bactericidal activity of these agents,and the targets of the three cephems were determined. The MICs of cefixime, cefpodoxime, and ceftibuten for 90% of the Amps and AmprBLP isolates were 0.04, 0.08, and 0.08 microgram/ml, respectively. In contrast, the MICs for 90% of the AmprNBLP strains were 0.96, 1.92, and 7.68 micrograms/ml. No significant inocul uM effect was observed for any group of strains comparing inocula of 10(3) and 10(5) CFU, whereas only the AmprNBLP isolates showed a marked effect at an inocul uM of 10(6) CFU. Although bactericidal levels were achieved for the Amps and AmprBLP strains, tolerance to cefixime and ceftibuten was observed. The bactericidal activity for the AmprNBLP strains was limited, with cefixime showing the highest activity of the three cephems. Penicillin-binding proteins 2, 4, and 5 revealedhigh affinity, with 50% inhibitory concentration levels below the MIC for all three cephems, suggesting that these are important targets of these agents in H. influenzae. We conclude that the cephemsare highly active in vitro against Amps and AmprBLP strains of H. influenzae, but less so against AmprNBLP isolates.	[39]
	Cefpodoxime	Drug Info	The antimicrobial activities of cefixime, cefpodoxime, and ceftibuten were determined with 18 ampicillin-susceptible (Amps), 13 ampicillin-resistant beta-lactamase-producing (AmprBLP), and 7 ampicillin-resistant non-beta-lactamase-producing (AmprNBLP) strains of Haemophilus influenzae. An effect of inocul uM density on apparent MIC, the bactericidal activity of these agents,and the targets of the three cephems were determined. The MICs of cefixime, cefpodoxime, and ceftibuten for 90% of the Amps and AmprBLP isolates were 0.04, 0.08, and 0.08 microgram/ml, respectively. In contrast, the MICs for 90% of the AmprNBLP strains were 0.96, 1.92, and 7.68 micrograms/ml. No significant inocul uM effect was observed for any group of strains comparing inocula of 10(3) and 10(5) CFU, whereas only the AmprNBLP isolates showed a marked effect at an inocul uM of 10(6) CFU. Although bactericidal levels were achieved for the Amps and AmprBLP strains, tolerance to cefixime and ceftibuten was observed. The bactericidal activity for the AmprNBLP strains was limited, with cefixime showing the highest activity of the three cephems. Penicillin-binding proteins 2, 4, and 5 revealedhigh affinity, with 50% inhibitory concentration levels below the MIC for all three cephems, suggesting that these are important targets of these agents in H. influenzae. We conclude that the cephemsare highly active in vitro against Amps and AmprBLP strains of H. influenzae, but less so against AmprNBLP isolates.	[39]
	Cefradine	Drug Info	Minimal inhibitory concentration (MIC) with nine antibiotics was determined on 188 isolates of S. pyogenes collected from outpatients with pharyngitis in four children's hospitals in different regions of China in 2007. MICs of penicillin, chloramphenicol, cefradine, levofloxacin, macrolide (erythromycin, clarithromycin, azithromycin,), clindamycin, and tetracycline were determined by the microdilution method. The macrolide resistant phenotypes of isolates were determined through a double-disk. The macrolide-resistant genes (mefA, ermB, and ermA) were amplified by polymerase chain reaction (PCR).Over 95% were resistant to macrolides, while 92.0% were resistant to tetracycline. We also found that all isolates were sensitive to penicillin, chloramphenicol, cefradine, and levofloxacin. Among the 173 erythromycin resistant strains, 171 (98.8%) were assigned to the cMLS phenotype, while the remaining 2 (1.2%) were assigned to the iMLS phenotype. Among the 171 cMLS isolates, 168 isolates (98.2%) had the ermB gene accounting for 98.2%. Meanwhile, 2 iMLS isolates had the ermA gene. Macrolides were highly resistant to ermB positive strains (MIC(90) > 256 microg/ml). Neither the M-phenotype nor the mefA gene was detected. Meanwhile, our studies of multiple centers showed that cons uMption of macrolides from 2000 to 2006 was very high.	[32]
	Ceftazidime	Drug Info	Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectr uM gram-negative activity observed with doripenem.IC50: 70 ng/mL	[25]
	Ceftibuten	Drug Info	The antimicrobial activities of cefixime, cefpodoxime, and ceftibuten were determined with 18 ampicillin-susceptible (Amps), 13 ampicillin-resistant beta-lactamase-producing (AmprBLP), and 7 ampicillin-resistant non-beta-lactamase-producing (AmprNBLP) strains of Haemophilus influenzae. An effect of inocul uM density on apparent MIC, the bactericidal activity of these agents,and the targets of the three cephems were determined. The MICs of cefixime, cefpodoxime, and ceftibuten for 90% of the Amps and AmprBLP isolates were 0.04, 0.08, and 0.08 microgram/ml, respectively. In contrast, the MICs for 90% of the AmprNBLP strains were 0.96, 1.92, and 7.68 micrograms/ml. No significant inocul uM effect was observed for any group of strains comparing inocula of 10(3) and 10(5) CFU, whereas only the AmprNBLP isolates showed a marked effect at an inocul uM of 10(6) CFU. Although bactericidal levels were achieved for the Amps and AmprBLP strains, tolerance to cefixime and ceftibuten was observed. The bactericidal activity for the AmprNBLP strains was limited, with cefixime showing the highest activity of the three cephems. Penicillin-binding proteins 2, 4, and 5 revealedhigh affinity, with 50% inhibitory concentration levels below the MIC for all three cephems, suggesting that these are important targets of these agents in H. influenzae. We conclude that the cephemsare highly active in vitro against Amps and AmprBLP strains of H. influenzae, but less so against AmprNBLP isolates.	[39]
	Chlorambucil	Drug Info	A n uMber of novel cyclic amidine analogs of chlorambucil were synthesized and examined for cytotoxicity in breast cancer cell cultures and for inhibition of topoisomerases I and II. Evaluation of the cytotoxicity of these compounds employing a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoli uM bromide assay and inhibition of [(3)H]-thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that these compounds were more active than chlorambucil. The degree to which these compounds inhibited cell growth breast cancer cells was directly correlated to DNA-binding affinity. These studies indicate that cyclic amidine analogs of chlorambucil are a potent catalytic inhibitor of topoisomerase II but not topoisomerase I. The highest degree of DNA binding and cytotoxicity in both MDA-MB-231 and MCF-7 breast cancer cells was observed for the compound, which possess a 4,5-dihydro-1H-imidazol moiety.	[13]
	Ciprofloxacin XR	Drug Info	MIC on Escherichia coli ATCC 25922 strain: 8 ng/mL	[21]
	Cisplatin	Drug Info	Gamma-linolenic acid (GLA) is known to have selective t uMoricidal action. It is also reported that GLA may increase the cytotoxic activity of cancer chemotherapeutic agents in some cancer cells. The present study examined whether GLA pretreatment could modulate the response of multidrug-resistant K562/ADM leukemic cells to anticancer drugs. The cell viability assay results showed that GLA at 10 microg/ml enhanced cell growth inhibition induced by the MDR-type drugs doxorubicin, etoposide and vincristine, but could not enhance or even attenuated cell growth inhibition induced by the non-MDR-type drug cisplatin, mitomycin and fluorouracil in K562/ADM cells. Further flow cytometry results showed that GLA decreased the expression of P-glycoprotein, enhanced the acc uMulation of doxorubicin and rhodamine 123 in K562/ADM cells and inhibited the efflux of rhodamine 123 from K562/ADM cells, lowered the efflux rate. These results suggest that GLA could modulate the response to anti-cancer agents in P-gp overexpressing multidrug-resistant cells, and the mechanism may be by decreasing the P-gp expression and inhibiting P-gp function.IC50: 900 ng/mL	[31]
	Clofarabine	Drug Info	Purine nucleoside antimetabolites, such as clofarabine, are effective antileukemic agents. However, their effectiveness depends on an initial activation step in which they are monophosphorylated by deoxycytidine kinase (dCK). Some purine nucleoside antimetabolites and their monophosphate derivatives are exported by the ABC transporter ABCG2. Because clofarabine is a dCK substrate, and we show substantial variation in dCK and ABCG2 in myeloid leukemia, we hypothesized that the activity of dCK may modulate ABCG2-mediated resistance to clofarabine by regulating the formation of clofarabine monophosphate. We show that ABCG2 influence on clofarabine cytotoxicity was markedly influenced by dCK activity. When dCK expression was reduced by siRNA, clofarabine cytotoxicity wasstrongly reduced by enhanced ABCG2-mediated efflux. Conversely, dCK overexpression blunted ABCG2-mediated efflux of clofarabine by increasing the formation of clofarabine nucleotides. The use of an ABCG2 inhibitor confirmed that ABCG2 export of clofarabine is maximal when dCK levels are minimal. Analysis of intracellular clofarabine metabolites suggested that ABCG2 exported clofarabine more readily than clofarabine monophosphate. That ABCG2 primarily effluxes clofarabine, but not chlorfarabine-monophosphate, was confirmed by HPLC analysis of drug exported from ABCG2-overexpressing cells. Because the level and function of dCK and ABCG2 vary substantially among other types of cancer, these findings have important implications not only for clofarabine therapy but for purine nucleoside therapy in general. Therefore, we propose that addition of ABCG2 inhibitors would effectively increase the antit uMor efficacy of purine nucleosides by blocking drug efflux that may be a significant mode ofresistance when dCK levels are low.	[38]
	Cyclophosphamide	Drug Info	The results obtained by Huntingdon Research Centre participating in a blind trial of the micromass assay for the prediction of teratogenic potential are presented. Twenty-five coded compounds were tested without S-9 mix using a pre-agreed protocol; three compounds were later tested with S-9. The data were assessed for sensitivity, specificity and accuracy using three separate sets of criteria based on either concentration (the <500 m ug/ml rule (i) and the <50 m ug/ml rule (ii)) or specific inhibition of cell differentiation at relatively non-cytotoxic concentrations (the 2-fold rule (iii)). The best in vivo/in vitro correlation was obtained using the 2-fold rule; the <500 m ug/ml rule was the most sensitive but gave a high false positive rate and the <50 m ug/ml rule was of low overall accuracy (60%). It is suggested that selective inhibition of differentiation of one cell type and cytotoxicity at low dose levels may also indicate risk of embryo-foeto toxicity, a factor to be considered with the pharmacokinetics of the compound. The teratogens procarbazine, methotrexate and caffeine were not detected; diphenhydramine and furazolidone initially classified as non-teratogens in vivo, were predicted as teratogens by the micromass assay.	[37]
	DTI-015	Drug Info	In vitro, GBM cells were treated with AS-C, and the cell proliferation, changes in distributions of cell cycle, and apoptosis were determined. In vivo, h uMan DBTRG-05MG and ratRG2 GBM t uMor cells were injected s.c. or i.c. and were treated with AS-C. Effects on t uMor growth were determined by t uMor vol uMe, magnetic resonance imaging, survival, and histology analysis.The AS-C displays potency in suppressing growth of malignant brain t uMor cells without cytotoxicity to fibroblasts. Growth suppression of malignant brain t uMor cells by AS-C results from cell cycle arrest and apoptosis. AS-C can up-regulate expression of cdk inhibitors, including p21, to decrease phosphorylation of Rb proteins resulting in cell arrest at the G0-G1 phase for DBTRG-05MG and RG2 cells. The apoptosis-associated proteins are dramatically increased and activated in DBTRG-05MG cells and RG2 cells by AS-C but RG2 cells without p53 protein expression. In vitro results showed AS-C triggered both p53-dependent and p53-independent pathways for apoptosis. In in vivo studies, AS-C not only can suppress growths of malignant brain t uMors of rat and h uMan origin but also shrink the vol uMes of in situ GBM, significantly prolonging survivals.	[17]
	Ertapenem	Drug Info	Ertapenem, a Group 1 carbapenem, is the most recent beta-lactam antibiotic to enter clinical practice in the USA and Europe. While structurally a carbapenem, the overall molecular structure of ertapenem has been modified to focus its antibacterial spectr uM on important community-acquired aerobic and anaerobic pathogens, and to increase its plasma half-life, permitting once-a-day dosing for this parenteral antibiotic. A n uMber of chemical features are responsible for the unique properties of ertapenem. The inclusion of a trans-1-hydroxyethyl group in the structure of ertapenem enables the drug to maintain antibacterial efficacy against the vast majority of beta-lactamase-producing organisms. A critical 1beta-methyl substituent shields the beta-lactam carbonyl group and serves to reduce dehydropeptidase (DHP)-1 catalysed hydrolysis of the beta-lactam, enabling ertapenem to be administered without a DHP-1 inhibitor. A meta-substituted benzoic acid substituent increases the molecular weight and lipophilicity of the molecule, and the carboxylic acid moiety, ionized at physiological pH, results in ertapenem having a net negative charge. As a result, ertapenem is highly protein bound and has an extended half-life, permitting a once-a-day treatment regimen.	[15]
	Furazolidone	Drug Info	The current treatment for leishmaniasis is unsatisfactory due to toxic side effects, high cost, and problems with drug resistance. Various approaches have been used to identify novel drug candidates to treat Leishmania sp. parasites including the use of re-purposed drugs. Furazolidone is a nitrofuran derivative with antiprotozoal and antibacterial activity and is used for the treatment of giardiasis. In the present work, we determined the in vitro antileishmanial activity of furazolidone and its ability to induce ultrastructural alterations of parasites. Promastigotes ofLeishmania (L.) chagasi, Leishmania (V.) braziliensis, Leishmania (L.) major, and Leishmania (L.) amazonensis were highly susceptible to furazolidone, with IC(50) values ranging between 0.47 and 0.73microg/mL. Furazolidone was also very effective against L. chagasi intracellular amastigotes, and despite mammalian cytotoxicity, the selectivity index was 8.0 in h uMan monocytes. The drug also had limited toxicity in mice erythrocytes. Furazolidone demonstrated specific activity against Leishmania, a potential consequence of the lack of macrophage nitric oxide activation. As determined by electron transmission microscopy, drug treatment induced severe damage to the parasite mitochondria and nucleus. This older oral drug is an effective agent for the treatment of L. (L.) chagasi in vitro andis a novel candidate for further experimental studies.	[35]
	Melphalan	Drug Info	A novel amidine analogue of melphalan (AB4) was compared to its parent drug, melphalan in respect to cytotoxicity, DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 h uMan breast cancer cells. It was found that AB4 was more active inhibitor of DNA and collagen synthesis as well more cytotoxic agent than melphalan. The topoisomerase I/II inhibition assay indicated that AB4 is a potent catalytic inhibitor of topoisomerase II. Data from the ethidi uM displacement assay showed that AB4 intercalated into the minor-groove at AT sequences of DNA. The greater potency of AB4 to suppress collagen synthesis was found to be accompanied by a stronger inhibition of prolidase activity and expression compared to melphalan. The phenomenon was related to the inhibition of beta(1)-integrin and IGF-I receptor mediated signaling caused by AB4. The expression of beta(1)-integrin receptor, as well as Sos-1 and phosphorylated MAPK, ERK(1) and ERK(2) but not FAK, Shc, and Grb-2 was significantly decreased in cells incubated for 24h with 20 microM AB4 compared to the control, not treated cells, whereas in the same conditions melphalan did not evoke any changes in expression of allthese signaling proteins, as shown by Western immunoblot analysis. These results indicate the amidine analogue of melphalan, AB4 represent multifunctional inhibitor of breast cancer cells growth and metabolism.	[19]
	Meropenem	Drug Info	Doripenem, a parenteral carbapenem, exhibited high affinity for penicillin-binding protein 2 (PBP2) and PBP3 in Pseudomonas aeruginosa and PBP2 in Escherichia coli, the primary PBPs whose inhibition leads to cell death. This PBP affinity profile correlates with the broad-spectr uM gram-negative activity observed with doripenem.IC50: 8 ng/mL	[25]
	Mitomycin	Drug Info	The one-electron reduction of redox-active chemotherapeutic agents generates highly toxic radical anions and reactive oxygen intermediates (ROI). A major enzyme catalyzing this process is cytochrome P450 reductase. Because many t uMor cells highly express this enzyme, redox cycling of chemotherapeutic agents in these cells may confer selective antit uMor activity. Nitrofurantoin is a commonly used redox-active antibiotic that possesses antit uMor activity. In the present studies we determined whether nitrofurantoin redox cycling is correlated with cytochrome P450 reductase activity and cytotoxicity in a variety of cell lines. Recombinant cytochrome P450 reductase was found to support redox cycling of nitrofurantoin and to generate superoxide anion, hydrogen peroxide,and, in the presence of redox-active iron, hydroxyl radicals. This activity was NADPH dependent and inhibitable by diphenyleneiodoni uM, indicating a requirement for the flavin cofactors in the reductase. Nitrofurantoin-induced redox cycling was next analyzed in different cell lines varying in cytochrome P450 reductase activity including Chinese hamster ovary cells (CHO-OR) constructed to overexpress the enzyme. Nitrofurantoin-induced hydrogen peroxide production was 16-fold greater in lysates from CHO-OR cells than from control CHO cells. A strong correlation between cytochrome P450 reductase activity and nitrofurantoin-induced redox cycling among the cell lines was found. Unexpectedly, no correlation between nitrofurantoin-induced ROI production and cytotoxicity was observed. These dataindicate that nitrofurantoin-induced redox cycling and subsequent generation of ROI are not sufficient to mediate cytotoxicity and that cytochrome P450 reductase is not a determinant of sensitivity to redox-active chemotherapeutic agents.	[6]
	Mitomycin	Drug Info	Gamma-linolenic acid (GLA) is known to have selective t uMoricidal action. It is also reported that GLA may increase the cytotoxic activity of cancer chemotherapeutic agents in some cancer cells. The present study examined whether GLA pretreatment could modulate the response of multidrug-resistant K562/ADM leukemic cells to anticancer drugs. The cell viability assay results showed that GLA at 10 microg/ml enhanced cell growth inhibition induced by the MDR-type drugs doxorubicin, etoposide and vincristine, but could not enhance or even attenuated cell growth inhibition induced by the non-MDR-type drug cisplatin, mitomycin and fluorouracil in K562/ADM cells. Further flow cytometry results showed that GLA decreased the expression of P-glycoprotein, enhanced the acc uMulation of doxorubicin and rhodamine 123 in K562/ADM cells and inhibited the efflux of rhodamine 123 from K562/ADM cells, lowered the efflux rate. These results suggest that GLA could modulate the response to anti-cancer agents in P-gp overexpressing multidrug-resistant cells, and the mechanism may be by decreasing the P-gp expression and inhibiting P-gp function.	[31]
	Nitrofurantoin	Drug Info	The one-electron reduction of redox-active chemotherapeutic agents generates highly toxic radical anions and reactive oxygen intermediates (ROI). A major enzyme catalyzing this process is cytochrome P450 reductase. Because many t uMor cells highly express this enzyme, redox cycling of chemotherapeutic agents in these cells may confer selective antit uMor activity. Nitrofurantoin is a commonly used redox-active antibiotic that possesses antit uMor activity. In the present studies we determined whether nitrofurantoin redox cycling is correlated with cytochrome P450 reductase activity and cytotoxicity in a variety of cell lines. Recombinant cytochrome P450 reductase was found to support redox cycling of nitrofurantoin and to generate superoxide anion, hydrogen peroxide,and, in the presence of redox-active iron, hydroxyl radicals. This activity was NADPH dependent and inhibitable by diphenyleneiodoni uM, indicating a requirement for the flavin cofactors in the reductase. Nitrofurantoin-induced redox cycling was next analyzed in different cell lines varying in cytochrome P450 reductase activity including Chinese hamster ovary cells (CHO-OR) constructed to overexpress the enzyme. Nitrofurantoin-induced hydrogen peroxide production was 16-fold greater in lysates from CHO-OR cells than from control CHO cells. A strong correlation between cytochrome P450 reductase activity and nitrofurantoin-induced redox cycling among the cell lines was found. Unexpectedly, no correlation between nitrofurantoin-induced ROI production and cytotoxicity was observed. These dataindicate that nitrofurantoin-induced redox cycling and subsequent generation of ROI are not sufficient to mediate cytotoxicity and that cytochrome P450 reductase is not a determinant of sensitivity to redox-active chemotherapeutic agents.	[24]
	Oxaliplatin	Drug Info	Approximately 70-80% of patients with metastatic testicular cancer will become disease free with cisplatin-based chemotherapy and most of these patients will be long-term survivors. Despite these impressive results, the two limitations of cisplatin are its severe and potentially long-term side-effects, and the emergence of drug resistance which prevents a small proportion ofthese patients from achieving long-term remission. Oxaliplatin has an improved toxicity profile compared to cisplatin and contains the diaminocyclohexane (DACH) substituent known to be correlated with a lack of cross-resistance with cisplatin. A phase II study has shown interesting activity when used in combination with cisplatin in cisplatin-refractory testicular cancer patients. Here we report the results of the first in vitro study investigating whether oxaliplatin as a single agent exhibits cross-resistance to cisplatin in a panel of non-seminomatous germ cell t uMor (NSGCT) cell lines using short and long-term drug exposures in a five-day sulfhodamine B in vitro cytotoxicity assay. Oxaliplatin cytotoxicity was significantly superior to cisplatin in cell lines with both acquired (H12DDP) and intrinsic (1777NRp Cl-A) intermediate level resistance to cisplatin. Following 24 h or 96 h drug exposure the fold resistance in H12DDP and 1777NRp Cl-A was 1.7-2.2 with oxaliplatin compared to 3.9-6.1 with cisplatin. The cytotoxic activity of oxaliplatin was not significantly different from that of cisplatin in cisplatin-sensitive cell lines or in cell lines with a high level (10-20 fold)of cisplatin resistance. The results of this study suggest that further preclinical studies in NSGCT are of interest, particularly in combination with cisplatin, ifosfamide and etoposide. Furthermore, the in vitro results support the use of an oxaliplatin administration schedule giving prolonged drug exposure, such as the flat or circadian rhythm-modulated schedule already under investigation foroxaliplatin.	[52]
	Primaquine	Drug Info	IC50 for Plasmodi uM falcipar uM isolates from Kericho, Kenya: 416 ng/mL	[16]
	Procarbazine	Drug Info	The results obtained by Huntingdon Research Centre participating in a blind trial of the micromass assay for the prediction of teratogenic potential are presented. Twenty-five coded compounds were tested without S-9 mix using a pre-agreed protocol; three compounds were later tested with S-9. The data were assessed for sensitivity, specificity and accuracy using three separate sets of criteria based on either concentration (the <500 m ug/ml rule (i) and the <50 m ug/ml rule (ii)) or specific inhibition of cell differentiation at relatively non-cytotoxic concentrations (the 2-fold rule (iii)). The best in vivo/in vitro correlation was obtained using the 2-fold rule; the <500 m ug/ml rule was the most sensitive but gave a high false positive rate and the <50 m ug/ml rule was of low overall accuracy (60%). It is suggested that selective inhibition of differentiation of one cell type and cytotoxicity at low dose levels may also indicate risk of embryo-foeto toxicity, a factor to be considered with the pharmacokinetics of the compound. The teratogens procarbazine, methotrexate and caffeine were not detected; diphenhydramine and furazolidone initially classified as non-teratogens in vivo, were predicted as teratogens by the micromass assay.	[37]
	Temozolomide	Drug Info	Currently, the most efficacious treatment for malignant gliomas is temozolomide; however, gliomas expressing the DNA repair enzyme O(6)-methylguanine-DNA methyltransferase (MGMT) are resistant to this drug. Strong clinical evidence shows that gliomas with methylation and subsequent silencing of the MGMT promoter are sensitive to temozolomide. Based on the fact that adenoviral proteins directly target and inactivate key DNA repair genes, we hypothesized that the oncolytic adenovirus Delta-24-RGD could be successfully combined with temozolomide to overcome the reported MGMT-mediated resistance. Our studies showed that the combination of Delta-24-RGD and temozolomide induces a profound therapeutic synergy in glioma cells. We observed that Delta-24-RGD treatment overrides the temozolomide-mediated G(2)-M arrest. Furthermore, Delta-24-RGD infection was followed by down-modulation of the RNA levels of MGMT. Chromatin immunoprecipitation assays showed that Delta-24-RGD prevented the recruitment of p300 to the MGMT promoter. Importantly, using mutant adenoviruses and wild-type and dominant-negative forms of the p300 protein, we showed that Delta-24-RGD interaction with p300 was required to induce silencing of the MGMT gene. Of further clinical relevance, the combination of Delta-24-RGD and temozolomide significantly improved the survival of glioma-bearing mice. Collectively, our data provide a strong mechanistic rationale for the combination of oncolytic adenoviruses and temozolomide, and should propel the clinical testing of this therapy approach in patientswith malignant gliomas.	[23]
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