-Fludarabine phosphate may be rapidly dephosphorylated by Phosphorylase cleavage to 2-fluoro-arabinosyladenine and then phosphorylated intracellularly by Deoxycytidine Kinase to the active triphosphate, 2-fluoro-arabinosyl-ATP.

Calicheamicin (ozogamicin) is released from the antibody inside the lysosomes of cells.

The abundance of nucleoside transporters on a tumor or host cell may be a major determinant of the amount of nucleoside or nucleoside analog that is taken up into a particular tissue type.

-Fludarabine phosphate may be rapidly dephosphorylated by Phosphorylase cleavage to 2-fluoro-arabinosyladenine and then phosphorylated intracellularly by Deoxycytidine Kinase to the active triphosphate, 2-fluoro-arabinosyl-ATP.

The combined use with fludarabine may lead to severe, even fatal, pulmonary toxicity.Fludarabine phosphate ([(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)-3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid, 2-fluoro-ara-AMP) <Fludara, Oforta> is a fluorinated analog of vidarabine.Fludarabine phosphate is susceptible to glycosidic bond cleavage, which results in the formation of 2-fluoro-adenine, and is further converted to the highly toxic 2-fluoro-ATP.Fludarabine phosphate may be rapidly dephosphorylated by Phosphorylase cleavage to 2-fluoro-arabinosyladenine and then phosphorylated intracellularly by Deoxycytidine Kinase to the active triphosphate, 2-fluoro-arabinosyl-ATP.

Similar in action to cytarabine, fazarabine is phosphorylated by Deoxycytidine Kinase to a triphosphate form, which competes with thymidine for incorporation into the DNA.

-Fludarabine phosphate may be rapidly dephosphorylated by Phosphorylase cleavage to 2-fluoro-arabinosyladenine and then phosphorylated intracellularly by Deoxycytidine Kinase to the active triphosphate, 2-fluoro-arabinosyl-ATP.

-This agent inhibits serine/threonine Protein Phosphatase type 2A (and to a lesser extent type 1) and Protein Phosphatase 4 (PP4), which leads to phosphorylation and reorganization of Vimentin filaments, thereby interfering with cellular proliferation.

At higher concentrations and longer exposure times, the slightly lipophilic agent clofarabine also enters cells by passive diffusion across lipid membranes.Clofarabine is phosphorylated by cytosolic kinases, including Deoxycytidine Kinase (DCK) and a Purine Nucleoside Monophosphate Kinase, to yield the active form clofarabine triphosphate.

At higher concentrations and longer exposure times, the slightly lipophilic agent clofarabine also enters cells by passive diffusion across lipid membranes.Clofarabine is phosphorylated by cytosolic kinases, including Deoxycytidine Kinase (DCK) and a Purine Nucleoside Monophosphate Kinase, to yield the active form clofarabine triphosphate.

The poly-glutamylation of anti-folates has been attempted to stabilize the compounds.Thymidylate Synthase inhibitors Thymidylate Synthase catalyzes the methylation of 2′-deoxyuridine-5′-monophosphate (dUMP) to 2′-deoxythymidine-5′monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate, an essential precursor in DNA synthesis (Fig. 2.42 ).

The poly-glutamylation of anti-folates has been attempted to stabilize the compounds.Thymidylate Synthase catalyzes the methylation of 2′-deoxyuridine-5′-monophosphate (dUMP) to 2′-deoxythymidine-5′-monophosphate (dTMP), which is subsequently phosphorylated to thymidine triphosphate, an essential precursor in DNA synthesis (Fig. 2.42).

This may reflect altered condensation with pyrophosphorylribose-5-phosphate (PRPP) or activation via the salvage pathway that involves ribose-1-phosphate or deoxyribose-1-phosphate and the appropriate Nucleoside Phosphorylase, with subsequent phosphorylation of the resultant nucleoside by Uridine Kinase or Thymidine Kinase.

6-Mercaptopurine is inactivated via two major pathways,thiol methylation is catalyzed by the highly polymorphic enzyme Thiopurine S-Methyltransferase (TPMT), to form methyl-6-mercaptopurine.oxidation is catalyzed by Xanthine Oxidase and forms 6-thiouric acid.The metabolic products are rapidly eliminated by the kidneys, with close to 50 % of the administered dose being excreted in the first 24 h.Bone marrow depression is the main toxic effect.

blocked, comprising the synthesis of tetrahydrofolate ( THF), 1-carbon donors (1 C donors), and the production of essential molecules for cell proliferation regulatory elements are associated with clinical outcome in the treatment of osteosarcoma or childhood acute lymphoblastic leukemia (ALL).

blocked, comprising the synthesis of tetrahydrofolate ( THF), 1-carbon donors (1 C donors), and the production of essential molecules for cell proliferation regulatory elements are associated with clinical outcome in the treatment of osteosarcoma or childhood acute lymphoblastic leukemia (ALL).

Ototoxicity (tinnitus and hearing loss) can lead to deafness.

Triaziquone produces myelosclerotic reactions with low frequency.P53 is a critical tumor suppressor protein that may arrest cell cycle progression or induce apoptosis.

Adverse Effects Triaziquone produces myelosclerotic reactions with low frequency.P53 is a critical tumor suppressor protein that may arrest cell cycle progression or induce apoptosis.

Possible adverse effects include nausea and vomiting , diarrhea , sore mouth , decreased white blood cell count , decreased platelet count , and infusion site burning .

Possible adverse effects include nausea and vomiting , diarrhea , sore mouth , decreased white blood cell count , decreased platelet count , and infusion site burning .

Ototoxicity (tinnitus and hearing loss) can lead to deafness.

Possible adverse effects include nausea and vomiting , diarrhea , sore mouth , decreased white blood cell count , decreased platelet count , and infusion site burning .

Possible adverse effects include nausea and vomiting , diarrhea , sore mouth , decreased white blood cell count , decreased platelet count , and infusion site burning .

- The active metabolite 5-fluoro-2 ' - deoxyuridine-5 ' - O-monophosphate ( F-dUMP ) , inhibits Thymidylate Synthase , resulting in the depletion of thymidine triphosphate ( TTP ) , a necessary constituent of DNA .

FdUMP inhibits DNA synthesis and cell division by reducing thymidine production.Several fluorouracil metabolites incorporate into both RNA and DNA .

FdUMP inhibits DNA synthesis and cell division by reducing thymidine production .

Possible adverse effects include nausea and vomiting , diarrhea , sore mouth , decreased white blood cell count , decreased platelet count , and infusion site burning .

Possible adverse effects include nausea and vomiting , diarrhea , sore mouth , decreased white blood cell count , decreased platelet count , and infusion site burning .

The occurrence of bone marrow suppression can cause neutropenia , which may lead to infections .

Some of the anti-neoplastic antibiotics also inhibit Topoisomerase 2 .

Antibiotics Some of the anti-neoplastic antibiotics also inhibit Topoisomerase 2 .

In an inactivation step, Carbonyl Reductase (AKR1B10) catalyzes the reduction of daunorubicin to the alcohol daunorubicinol.

In an inactivation step, Carbonyl Reductase (AKR1B10) catalyzes the reduction of daunorubicin to the alcohol daunorubicinol.The clinical use of anthracycline antibiotics is hampered by toxicity in healthy tissues.

Doxifluridine ( 5 ' - deoxy-5-fluorouridine ) is a fluoropyrimidine derivative and oral prodrug of 5-fluorouracil , designed to circumvent the rapid degradation of 5-fluorouracil by Dihydropyrimidine Dehydrogenase in the gut wall and liver .

Doxifluridine (5′-deoxy-5-fluorouridine) is a fluoropyrimidine derivative and oral prodrug of 5-fluorouracil, designed to circumvent the rapid degradation of 5-fluorouracil by Dihydropyrimidine Dehydrogenase in the gut wall and liver.

Doxifluridine ( 5 ' - deoxy-5-fluorouridine ) is a fluoropyrimidine derivative and oral prodrug of 5-fluorouracil , designed to circumvent the rapid degradation of 5-fluorouracil by Dihydropyrimidine Dehydrogenase in the gut wall and liver .

Carbonyl Reductase ( CBR ) catalyzes the reduction of daunorubicin to its corresponding alcohol , daunorubicinol , which changes the pharmacological properties of this cancer chemotherapeutic drug .

Pharmacokinetics Carbonyl Reductase ( CBR ) catalyzes the reduction of daunorubicin to its corresponding alcohol , daunorubicinol , which changes the pharmacological properties of this cancer chemotherapeutic drug .

Liposomal daunorubicin is under investigation for the treatment of AIDSrelated Kaposi sarcoma, acute myeloblastic leukemia, multiple myeloma, non-Hodgkin lymphoma, and breast cancer.Pharmacokinetics Carbonyl Reductase (CBR) catalyzes the reduction of daunorubicin to its corresponding alcohol, daunorubicinol, which changes the pharmacological properties of this cancer chemotherapeutic drug.

The mean terminal elimination half-life of the active metabolite SN-38 is 10–20 h. SN-38 is inactivated via glucuronidation by UGT1A1 (Uridine Diphosphate Glucoronosyltransferase 1A1) into the non-toxic SN-38-glucuronide (SN-38G) and is excreted into the gastrointestinal tract.The most substantial adverse effects of irinotecan are grade 2 or higher nausea and vomiting, alopecia, asthenia, fever, and abdominal pain.

The mean terminal elimination half-life of the active metabolite SN-38 is 10-20 h. SN-38 is inactivated via glucuronidation by UGT1A1 (Uridine Diphosphate Glucoronosyltransferase 1A1) into the non-toxic SN-38-glucuronide (SN-38G) and is excreted into the gastrointestinal tract.Adverse Effects The most substantial adverse effects of irinotecan are grade 2 or higher nausea and vomiting, alopecia, asthenia, fever, and abdominal pain.

Thymidylate Synthase inhibitors Thymidylate Synthase catalyzes the methylation of 2 ' - deoxyuridine-5 ' - monophosphate ( dUMP ) to 2 ' - deoxythymidine-5'monophosphate ( dTMP ) , which is subsequently phosphorylated to thymidine triphosphate , an essential precursor in DNA synthesis ( Fig. 2.42 ) .

Bleomycin is inactivated by the cytosolic Aminohydrolase (Bleomycin Hydrolase).

blocked, comprising the synthesis of tetrahydrofolate ( THF), 1-carbon donors (1 C donors), and the production of essential molecules for cell proliferation regulatory elements are associated with clinical outcome in the treatment of osteosarcoma or childhood acute lymphoblastic leukemia (ALL).

blocked, comprising the synthesis of tetrahydrofolate ( THF), 1-carbon donors (1 C donors), and the production of essential molecules for cell proliferation regulatory elements are associated with clinical outcome in the treatment of osteosarcoma or childhood acute lymphoblastic leukemia (ALL).

Although camptothecin and its analogs can freely enter cells via passive diffusion , their intracellular concentrations are greatly reduced by efflux pumps .

Drug Resistance Although camptothecin and its analogs can freely enter cells via passive diffusion , their intracellular concentrations are greatly reduced by efflux pumps .

Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase .

The therapeutic index of bis ( sulfonyl ) hydrazine compounds may therefore be more favorable.Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase .

It inhibits Topoisomerase 2, thereby blocking DNA reduplication and RNA synthesis.Razoxane (ICRF 159, ICI 59118) <Razoxin> is a bisdioxopiperazine and a derivative of the chelating agent EDTA.

The drug is an intercalator and a Topoisomerase 2 inhibitor that prevents DNA reduplication and ultimately inhibits protein synthesis.

They share a polycyclic aromatic core structure.The 2 main modes of anthracycline action comprise Topoisomerase inhibition and generation of reactive oxygen species.Because first generation anthracyclines are associated with myocardial dysfunction and alopecia, second generation drugs attempt to reduce these adverse effects.Because of enhanced total body clearance, epirubicin can be used at high cumulative doses without increased cardiotoxicity.Oligosaccharide anthracyclines induce hematopoietic differentiation.The diaminoalkyl groups are crucial for the biological activity of anthracenediones.

Platelet counts may drop.Drug Resistance Treatment with verapamil may reduce resistance to tallimustine.MEN 10710 is a synthetic distamycin derivative that possesses four methyl-pyrrole rings and a bis-(2-chloroethyl) aminophenyl moiety linked to the oligopyrrole backbone by a flexible butanamido chain.Brostallicin (PNU-166196) is a bromo-acrylamido tetrapyrrole distamycin derivative with high cytotoxic potency.

Streptozotocin can reduce the tumor burden and ameliorate symptoms , such as hypoglycemia due to excessive Insulin secretion by insulinomata .

Methotrexate ((S)-2-(4-(((2,4-diaminopteridin-6-yl) methyl)methylamino)benzamido) pentanedioic acid, mtx, amethopterin, MTX) <Trexall> binds to, and competitively and reversibly inhibits the enzyme Dihydrofolate Reductase.

Procarbazine inhibits MAO thus increasing the effects of sympathomimetics , tricyclic anti-depressants , and tyramine ( hypertensive crisis can be caused by the ingestion of tyramine-rich food ) .

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.

The agent can be effectively combined with other nucleoside analogs, particularly clofarabine and gemcitabine, which inhibit Ribonucleotide Reductase.Other pyrimidine antagonists Penclomedine (3,5-dichloro -2,4-dimethoxy-6 trichloromethyl pyridine) (NSC338720) is a synthetic derivative of pyrimidine that alkylates and crosslinks DNA, resulting in DNA strand breaks and inhibition of DNA and RNA synthesis.

The agent can be effectively combined with other nucleoside analogs, particularly clofarabine and gemcitabine, which inhibit Ribonucleotide Reductase.Other pyrimidine antagonists Penclomedine (3,5-dichloro -2,4-dimethoxy-6 trichloromethyl pyridine) (NSC338720) is a synthetic derivative of pyrimidine that alkylates and crosslinks DNA, resulting in DNA strand breaks and inhibition of DNA and RNA synthesis.

Dietary folates must be chemically reduced to their tetrahydro-forms, bearing four hydrogens on the pteridine ring, to be active.

In the presence of folates, fluorodeoxyuridine monophosphate binds tightly to and interferes with the function of Thymidylate Synthase, resulting in decreased thymidine synthesis and consecutively reduced DNA synthesis.

The parent compound also releases a thiophilic carbamoylating methyl isocyanate, which inhibits the DNA repair enzyme O6-Alkyl-Guanine Transferase.

The parent compound also releases a thiophilic carbamoylating methyl isocyanate, which inhibits the DNA repair enzyme O 6 -Alkyl-Guanine Transferase.

Among the transcription factors down-regulated by olivomycin A is c-MYC, a major regulator of DNA synthesis and cell survival.The drug effect is not dependent on P53, which implies efficacy in cancers with loss of function in P53.Chromomycin A3 (toyomycin, aburamycin) is a fermentation product of Streptomyces griseus.

Among the transcription factors downregulated by olivomycin A is c-MYC, a major regulator of DNA synthesis and cell survival.Drug Resistance The drug effect is not dependent on P53, which implies efficacy in cancers with loss of function in P53.Chromomycin A3 (toyomycin, aburamycin) is a fermentation product of Streptomyces griseus.

Mitoxantrone hydrochloride (DHAD, 1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl) amino]ethyl]amino]-9,10-anthracenedione dihydrochloride) (NSC-29919) <Novantrone> intercalates into and cross-links DNA, thereby disrupting DNA reduplication and RNA synthesis.

Razoxane inhibits Topoisomerase 2 without inducing DNA strand breaks, thereby inhibiting DNA synthesis and inducing cytotoxicity.

Razoxane inhibits Topoisomerase 2 without inducing DNA strand breaks , thereby inhibiting DNA synthesis and inducing cytotoxicity .

Also shaded in pink are the nitrogen substitutions of the base in fazarabine and decitabine blocks thymidylate synthesis.

The agent is lipophilic.Metoprine (DDMP, 2,4-diamino-5-(3′,4′-dichlorophenyl)-6-methylpyrimidine) (BW 197U) is a diaminopyrimidine folate antagonist that inhibits Dihydrofolate Reductase, resulting in decreased cellular folate metabolism and cell growth.

Drug Resistance The clinical use of anthracycline antibiotics is hampered by the development of resistance in tumor cells, which may be due to an over-expression of ABCB1 (MDR1, PGP), increased levels of enzymes that protect form reactive oxygen damage, activation of the transcription factor NF-κB that exerts crucial functions in cellular resistance to oxidants, altered topoisomerase 2 gene expression or activity, or enzymatic drug inactivation.The anthracycline daunorubicin was originally isolated from bacteria in soil samples taken from the Italian castle Castel del Monte.

Because aminosalicylate derivatives may inhibit the enzyme Thiopurine S-Methyltransferase (TPMT) they should be administered with caution to patients on 6-mercaptopurine therapy.The mercaptopurine derivative methylthioinosine (6-(methylmercapto)purine riboside, 6-MMPR) inhibits Amidophosphoribosyl Transferase, the first committed step in de novo purine synthesis, and inhibits cell proliferation induced by Fibroblast Growth Factor-2 (FGF-2).

Because aminosalicylate derivatives may inhibit the enzyme Thiopurine S-Methyltransferase (TPMT) they should be administered with caution to patients on 6-mercaptopurine therapy.The mercaptopurine derivative methylthioinosine (6-(methylmercapto)purine riboside, 6-MMPR) inhibits Amidophosphoribosyl Transferase, the first committed step in de novo purine synthesis, and inhibits cell proliferation induced by Fibroblast Growth Factor-2 (FGF-2).

A structural analog of p-aminobenzoic acid ( PABA ) , dapsone inhibits Dihydropteroate Synthase , resulting in a depletion of the folate pool and a reduction in the amount of thymidylate available for DNA synthesis .

Cyclophosphamide treatment, which causes a marked and persistent inhibition of Cholinesterase activity, potentiates the effect of succinylcholine chloride.

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy .

Allopurinol may diminish the rate of 6-mercaptopurine degradation by competing for the oxidizing enzymes that are part of the inactivating pathway , specifically the Xanthine Oxidase mediated degradation to thiouric acid .

The compound of arabinose and cytosine is metabolized by Deoxycytidine Kinase and other nucleotide kinases to a nucleotide triphosphate, which is an effective inhibitor of DNA Polymerase A and competes with thymidine for incorporation into DNA.

The compound of arabinose and cytosine is metabolized by Deoxycytidine Kinase and other nucleotide kinases to a nucleotide triphosphate, which is an effective inhibitor of DNA Polymerase A and competes with Fig. 2.46 Pathways of 5-fluorouracil metabolism.

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.Clofarabine triphosphate inhibits Ribonucleotide Reductase, leading to a depletion of the deoxyribonucleotide triphosphate (dNTP) pools.Clofarabine induces apoptosis through direct and indirect action on mitochondria by releasing Cytochrome c and other pro-apoptotic factors, including AIF (Apoptosis Inducing Factor), APAF-1 (Apoptotic Protease Activating Factor-1), and Caspase-9.The agent received accelerated approval from the U.S. FDA in 2004.

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.Clofarabine triphosphate inhibits Ribonucleotide Reductase, leading to a depletion of the deoxyribonucleotide triphosphate (dNTP) pools.Clofarabine induces apoptosis through direct and indirect action on mitochondria by releasing Cytochrome c and other pro-apoptotic factors, including AIF (Apoptosis Inducing Factor), APAF-1 (Apoptotic Protease Activating Factor-1), and Caspase-9.The agent received accelerated approval from the U.S. FDA in 2004.

The agent is activated to its triphosphate inside the tumor cells.-Clofarabine acts by terminating DNA chain elongation and inhibiting DNA repair through incorporation into the DNA.

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.

Because of the bone marrow suppression, vaccinations during or shortly before or shortly after chemotherapy with mechlorethamine should be avoided.Drug Interactions Turmeric may decrease the effect of mechlorethamine.

Nitrogen mustard also damages DNA through the production of reactive nitrogen species .

Cimetidine is an inhibitor of microsomal drug metabolism that may increase the half-life and toxicity of hexamethylmelamine.Water soluble analogs of hexamethylmelamine have been produced because of gastrointestinal adverse effects associated with the oral administration of the water insoluble preparation.

Tegafur competes with uridine triphosphate, thus inhibiting RNA and protein synthesis.

Because of this sequence selectivity, mithramycin A blocks the binding of the SP-1 family of transcription factors to C/G-rich sequences in gene promoters and inhibits gene transcription, which in turn alters the regulation of cell proliferation and differentiation.

These carboplatin induced DNA and protein effects result in apoptosis and cell growth inhibition.

These carboplatin induced DNA and protein effects result in apoptosis and cell growth inhibition.

Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase.ThioTEPA ( N, N′,N′-triethylenethiophosphoramide) <Thio-plex> was first developed by American Cyanamid in the early 1950s.

Hence the drug efficacy can potentially be enhanced by Helicase inhibitors.Illudins and acylfulvenes alkylate DNA, inhibit DNA synthesis, and deplete thiol anti-oxidant defenses.In 1965, cisplatin was discovered by Barnett Rosenberg, who explored the effects of electric fields on the growth of Escherichia coli bacteria (Rosenberg 1965) .

The inhibition of Adenosine Deaminase by deoxycoformycin leads to an intracellular accumulation of deoxy-ATP, which causes apoptosis.

Camptothecin also inhibits RNA synthesis.Irinotecan is an S phase specific agent.Camptothecins exist in a pH dependent equilibrium between their active lactone and inactive ring-opened conformations.The stability of the lactone ring at physiological pH is a determinant of activity for all camptothecin analogs.Topotecan and irinotecan are substrates for the efflux pump ABCB1.

Camptothecin also blocks RNA synthesis through Topoisomerase 1 mediated effects.Because camptothecin exists in equilibrium between the lactone and the ring-opened conformations its drug action is limited.

Camptothecin also blocks RNA synthesis through Topoisomerase 1 mediated effects.Pharmacokinetics Because camptothecin exists in equilibrium between the lactone and the ring-opened conformations its drug action is limited.

Mitomycin C at high concentrations also inhibits RNA and protein synthesis.

Mitomycin C at high concentrations also inhibits RNA and protein synthesis .

The coupling to a styrene maleic acid based polymer reduces the immunogenicity of neocarzinostatin.

Triaziquone produces myelosclerotic reactions with low frequency.P53 is a critical tumor suppressor protein that may arrest cell cycle progression or induce apoptosis.

Thus, the effects of inosine dialdehyde are different from those caused by typical inhibitors of Ribonucleotide Reductase, which rapidly suppress DNA synthesis and cause arrest of the cells in G1, with minimal effects on RNA and protein synthesis.In salvage pathways, nucleotides are synthesized from intermediates of canonical degradative pathways.

Thus, the effects of inosine dialdehyde are different from those caused by typical inhibitors of Ribonucleotide Reductase, which rapidly suppress DNA synthesis and cause arrest of the cells in G 1 , with minimal effects on RNA and protein synthesis.In salvage pathways, nucleotides are synthesized from intermediates of canonical degradative pathways.

This metabolite inhibits DNA Polymerase α, Ribonucleotide Reductase, and DNA Primase, thereby interrupting DNA synthesis and inhibiting tumor cell growth.Fludarabine is used in the treatment of hematologic malignancies.

This metabolite inhibits DNA Polymerase alpha , Ribonucleotide Reductase , and DNA Primase , thereby interrupting DNA synthesis and inhibiting tumor cell growth .

This metabolite inhibits DNA Polymerase alpha , Ribonucleotide Reductase , and DNA Primase , thereby interrupting DNA synthesis and inhibiting tumor cell growth .

It is given at 50-70 mg/ m 2 by intravenous bolus every 3-4 weeks.Adverse Effects The limiting toxicity of lobaplatin is thrombocytopenia, with a nadir at approximately 2 weeks after drug administration.

Nausea, vomiting, diarrhea, and an elevation of hepatic enzymes and bilirubin occur less often.Trimetrexate glucuronate (TMQ, 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyanilino)methyl] quinazoline mono-D-glucuronate) <Neutrexin> is a lipid soluble methotrexate derivative that inhibits Dihydrofolate Reductase.

These drugs inhibited adenine metabolism and later played an important role in the treatment of acute leukemia .

The drug intercalates into DNA and interacts with Topoisomerase 2 , thereby inhibiting DNA reduplication and repair , as well as RNA and protein synthesis .

The drug suppresses the expression of genes coding for transcription factors , heat shock proteins , and DNA repair proteins .

Unlike methotrexate, edatrexate has additive activity when used with cisplatin.Talotrexin ammonium (N(α )-(4-amino-4-deoxypteroyl)- N(δ)-hemiphthaloyl-L-ornithine) (PT523) <Talvesta> is a non-polyglutamable anti-metabolite analog of aminopterin that binds to and inhibits the function of Dihydrofolate Reductase.

6-Mercaptopurine can inhibit the anti-coagulant effect of warfarin, when given simultaneously.

In cancer cells that lack functional P53, DZQ mediated p21 induction is greatly diminished.

The coupling to a styrene maleic acid based polymer reduces the immunogenicity of neocarzinostatin.

Its cytotoxicity is not affected by disruption of P53 function or loss of DNA repair.In the presence of divalent cations, aureolic acid antibiotics form dimers that non-intercalatively bind to the DNA minor groove in high-GC-content regions.Upon binding to DNA, the aureolic acid chromophores form hydrogen bonds with NH2 residues of guanines.Mithramycin A binds to C/G-rich tracts as a dimer and blocks SP-1 family transcription factors.Ecteinascidin-743 effects guanine N2 alkylation.After intravenous administration, mitomycin C is rapidly cleared from the blood with a half-life of about 15 min.

Gemcitabine may temporarily reduce the number of white blood cells , particularly during the first 10-14 days after administration .

The agent can be effectively combined with other nucleoside analogs, particularly clofarabine and gemcitabine, which inhibit Ribonucleotide Reductase.Other pyrimidine antagonists Penclomedine (3,5-dichloro -2,4-dimethoxy-6 trichloromethyl pyridine) (NSC338720) is a synthetic derivative of pyrimidine that alkylates and crosslinks DNA, resulting in DNA strand breaks and inhibition of DNA and RNA synthesis.

The agent can be effectively combined with other nucleoside analogs, particularly clofarabine and gemcitabine, which inhibit Ribonucleotide Reductase.Penclomedine (3,5-dichloro-2,4-dimethoxy-6 trichloromethyl pyridine) (NSC338720) is a synthetic derivative of pyrimidine that alkylates and cross-links DNA, resulting in DNA strand breaks and inhibition of DNA and RNA synthesis.

The agent can be effectively combined with other nucleoside analogs, particularly clofarabine and gemcitabine, which inhibit Ribonucleotide Reductase.Other pyrimidine antagonists Penclomedine (3,5-dichloro -2,4-dimethoxy-6 trichloromethyl pyridine) (NSC338720) is a synthetic derivative of pyrimidine that alkylates and crosslinks DNA, resulting in DNA strand breaks and inhibition of DNA and RNA synthesis.

Because of its higher concentration in the combination, uracil saturates the uracil reducing enzymatic activity of Ddihydropyrimidine Ddehydrogenase, thereby inhibiting first pass hepatic metabolism of 5-fluorouracil and permitting its administration as the orally bioavailable prodrug tetrahydrofuranyl-5-fluorouracil.

The agent can be effectively combined with other nucleoside analogs, particularly clofarabine and gemcitabine, which inhibit Ribonucleotide Reductase.Other pyrimidine antagonists Penclomedine (3,5-dichloro -2,4-dimethoxy-6 trichloromethyl pyridine) (NSC338720) is a synthetic derivative of pyrimidine that alkylates and crosslinks DNA, resulting in DNA strand breaks and inhibition of DNA and RNA synthesis.

The neurotoxicity can be reduced by intake of pyridoxine ( vitamin B6 ) , however , it adversely affects the response duration .

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.

It acts at an essential step along the de novo path of pyrimidine biosynthesis by inhibiting Orotidylate Decarboxylase, which suppresses the formation of uridylic acid from its carboxylated precursor, orotidylic acid.

FUMP is further metabolized to FUTP, which inhibits RNA and protein synthesis by competing with uridine triphosphate for incorporation into the RNA strand, thereby suppressing cell growth.

The therapeutic index of bis(sulfonyl)hydrazine compounds may therefore be more favorable.Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase.

-Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase.

Their activation occurs with the release of the single-bonded nitrogen, leaving the highly reactive double-bonded diazonium fragment exposed.Oral availability and penetration of the blood-brain barrier vary among triazenes.The bis(sulfonyl)hydrazines are alkylating agents that produce chloroethylating species.Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase.Because absorption from the gastrointestinal tract is variable, thioTEPA should not be administered orally.

The therapeutic index of bis(sulfonyl)hydrazine compounds may therefore be more favorable.Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase.

Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase.ThioTEPA ( N, N′,N′-triethylenethiophosphoramide) <Thio-plex> was first developed by American Cyanamid in the early 1950s.

-Methyl benzyl hydrazine derivatives can suppress mitosis by prolonging interphase.

Also shaded in pink are the nitrogen substitutions of the base in fazarabine and decitabine blocks thymidylate synthesis.

Edatrexate inhibits Thymidylate Synthase and Glycinamide Ribonucleotide Formyl Transferase, impairing the synthesis of purine nucleotides and amino acids, and resulting in tumor cell death.

Edatrexate inhibits Thymidylate Synthase and Glycinamide Ribonucleotide Formyl Transferase, impairing the synthesis of purine nucleotides and amino acids, and resulting in tumor cell death.

Edatrexate inhibits Thymidylate Synthase and Glycinamide Ribonucleotide Formyl Transferase , impairing the synthesis of purine nucleotides and amino acids , and resulting in tumor cell death .

Edatrexate inhibits Thymidylate Synthase and Glycinamide Ribonucleotide Formyl Transferase, impairing the synthesis of purine nucleotides and amino acids, and resulting in tumor cell death.

Thereby exatecan inhibits DNA reduplication and triggers apoptotic cell death .

As a Topoisomerase 2 inhibitor and intercalating agent , elliptinium stabilizes the cleavable complex of Topoisomerase 2 and induces DNA breakages , thereby inhibiting DNA reduplication and RNA synthesis .

It is associated with the production of the neurotoxic metabolite chloroacetaldehyde.Dose fractionation and hydration aid substantially in limiting the toxicities of ifosfamide.

Hence the drug efficacy can potentially be enhanced by Helicase inhibitors.Illudins and acylfulvenes alkylate DNA, inhibit DNA synthesis, and deplete thiol anti-oxidant defenses.In 1965, cisplatin was discovered by Barnett Rosenberg, who explored the effects of electric fields on the growth of Escherichia coli bacteria (Rosenberg 1965) .

Liposomal PEGylated forms of daunorubicin have been designed to increase the amount of drug delivered to tumors and decrease the peak distribution to the heart and gastrointestinal mucosa.

3,6-diaziridinyl-1,4benzoquinone (DZQ) causes the increased expression of P21 CIP1/WAF1 , an inhibitor of Cyclin-Dependent Kinases.

3,6-diaziridinyl-1,4-benzoquinone (DZQ) causes the increased expression of P21CIP1/WAF1, an inhibitor of Cyclin-Dependent Kinases.

-Fludarabine phosphate may be rapidly dephosphorylated by Phosphorylase cleavage to 2-fluoro-arabinosyladenine and then phosphorylated intracellularly by Deoxycytidine Kinase to the active triphosphate, 2-fluoro-arabinosyl-ATP.

-Fludarabine phosphate may be rapidly dephosphorylated by Phosphorylase cleavage to 2-fluoro-arabinosyladenine and then phosphorylated intracellularly by Deoxycytidine Kinase to the active triphosphate, 2-fluoro-arabinosyl-ATP.

After uptake, it is O-demethylated by Adenosine Deaminase to ara-G, mono-phosphorylated by Deoxyguanosine Kinase and Deoxycytidine Kinase, and subsequently converted to the biologically active 9-β-D-arabinosylguanine 5′-triphosphate (ara-GTP).

It displays an acceptable safety profile.Sensitive tumor cells convert the prodrug 6-mercaptopurine to thioinosinate and 6-methylthioinosinate, which inhibit Glutamine-5-Phosphoribosylpyrophosphate Amidotransferase, the first enzyme unique to the de novo synthesis pathway for purine ribonucleotides.The Adenosine Deaminase (ADA) inhibitor co-vidarabine is effective against several lymphoproliferative conditions, but not acute lymphocytic leukemia because the transformed cells contain too high levels of Adenosine Deaminase.After uptake, nelarabine is O-demethylated by Adenosine Deaminase to ara-G, mono-phosphorylated by Deoxyguanosine Kinase and Deoxycytidine Kinase, and subsequently converted to the biologically active 9-β-D-arabinosylguanine 5′-triphosphate (ara-GTP).

Non-steroidal anti-inflammatory drugs (NSAIDs) and probenecid reduce the tubular secretion of methotrexate.

Forodesine binds preferentially to and inhibits Purine Nucleotide Phosphorylase, resulting in the accumulation of deoxyguanosine triphosphate, the subsequent inhibition of the enzyme Ribonucleoside Diphosphate Reductase49, and the abrogation of DNA synthesis.

Phenylbutazone, sodium salicylate, and aspirin can displace Albumin bound etoposide.

Estramustine and its major metabolite bind covalently to microtubule-associated proteins (MAPs) and Tubulin, thereby causing their separation from the microtubules, inhibiting microtubule assembly, and eventually causing their disassembly.Estramustine is taken orally, at least 1 h before or 2 h after meals.

Functional groups that differ from the parent compound, daunorubicin, are highlighted in pink cline and HCHO then react to form a conjugate, in which two anthracycline molecules bind together with three methylene groups, two forming oxazolidine rings and one binding the oxazolidines together at their 3′-amino nitrogens.

Due to the affinity of PtII for sulfur binding, platinum drugs can bind to Glutathione, Metallothionein, and serum Albumin.

Due to the affinity of PtII for sulfur binding, platinum drugs can bind to Glutathione, Metallothionein, and serum Albumin.

The mechanism of action involves the drug binding to CD33 antigen on the AML cell membrane, then being internalized.

The drug is Pregnancy Category D.Drug Interactions Drug interaction with cimetidine, amphotericin B, digoxin, or phenytoin may arise and require adjust-ment.

It depends on binding of a bleomycin/iron complex to DNA, which then reduces molecular oxygen to free oxygen radicals that cause primarily single strand breaks.Bleomycin sulfate <Blenoxane, Teva> is used in the treatment of Hodgkin and non-Hodgkin lymphoma as a component of the ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen, of squamous cell carcinoma, and of testicular cancer.

Due to the affinity of PtII for sulfur binding, platinum drugs can bind to Glutathione, Metallothionein, and serum Albumin.

ABCC2 (ATP-Binding Cassette sub-family C 2, MRP2, cMOAT) also has a role in cisplatin resistance, presumably by promoting drug efflux.

ABCC2 (ATP-Binding Cassette sub-family C 2, MRP2, cMOAT) also has a role in cisplatin resistance, presumably by promoting drug efflux.increased cytoplasmic detoxification through cellular thiols such as Glutathione (GSH).

Major binding interactions between the apoprotein and the chromophore are the hydrophobic contacts between the core of the chromophore and the hydrophobic side chains of the pocket forming residues.Neocarzinostatin (zinostatin, vinostatin), discovered in 1964, was the first enediyne antibiotic used clinically and has become a prototypical anti-cancer agent for the treatments of leukemia, gastric carcinoma and pancreatic adenocarcinoma.

Cardiac toxicity may cause tachycardia or left ventricular systolic dysfunction .

Cardiac toxicity may cause tachycardia or left ventricular systolic dysfunction.Nelarabine (506U78) <Arranon, Atriance> is an arabinonucleoside anti-metabolite prodrug.

Triaziquone produces myelosclerotic reactions with low frequency.P53 is a critical tumor suppressor protein that may arrest cell cycle progression or induce apoptosis.

Adverse Effects Triaziquone produces myelosclerotic reactions with low frequency.P53 is a critical tumor suppressor protein that may arrest cell cycle progression or induce apoptosis.

- Anthracyclines can directly release Cytochrome c from the mitochondria , thereby inducing apoptosis regardless of DNA damage , active signaling pathways , or P53 status .

- Anthracyclines can directly release Cytochrome c from the mitochondria , thereby inducing apoptosis regardless of DNA damage , active signaling pathways , or P53 status .

Uracil mustard may rarely cause stomatitis, associated with considerable discomfort.Uracil mustard can raise the concentration of blood uric acid.

In 1972 , when the Lasker Prize was awarded to investigators who had contributed to studies of 36 Aminopterin was synthesized by Yellapragada Subbarao at Lederle Laboratories .

Severe pancytopenia can arise and sometimes lead to death .

Severe pancytopenia can arise and sometimes lead to death.

Patients may experience myelosuppression , including prolonged pancytopenia , which can result in aplastic anemia .

It acts at an essential step along the de novo path of pyrimidine biosynthesis by inhibiting Orotidylate Decarboxylase , which suppresses the formation of uridylic acid from its carboxylated precursor , orotidylic acid .

Other adverse effects include mild nausea and vomiting during treatment, bone marrow hypoplasia, nephrosis, emesis, and bloody diarrhea.Prior treatment with a nitrosourea enhances the hematopoietic toxicity of indicine-N-oxide.Dianhydrogalactitol (1,2:5,6-diepoxyhexane-3,4-diol, 1,2-di(oxiranyl)ethylene glycol, dulcitol diepoxide, DAG) (NSC 132313) is a bifunctional hexitol diepoxide that was developed in Budapest (Nemeth et al. 1972).

The drug administered intrapleurally , intraperitoneally , or 7 A myeloproliferative disorder that results in the over-production of red blood cells .

Adverse effects include hemolysis , which may lead to hemolytic anemia , and methemoglobinemia .

Dapsone has been used to treat Kaposi sarcoma.Adverse effects include hemolysis, which may lead to hemolytic anemia, and methemoglobinemia.

Dapsone has been used to treat Kaposi sarcoma.Adverse Effects Adverse effects include hemolysis, which may lead to hemolytic anemia, and methemoglobinemia.

Adverse Effects Adverse effects include hemolysis , which may lead to hemolytic anemia , and methemoglobinemia .

Acidic pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form.

Dapsone has been used to treat Kaposi sarcoma.Adverse effects include hemolysis, which may lead to hemolytic anemia, and methemoglobinemia.

Dapsone has been used to treat Kaposi sarcoma.Adverse Effects Adverse effects include hemolysis, which may lead to hemolytic anemia, and methemoglobinemia.

Adverse effects include hemolysis , which may lead to hemolytic anemia , and methemoglobinemia .

Adverse Effects Adverse effects include hemolysis , which may lead to hemolytic anemia , and methemoglobinemia .

Genetic testing can predict this toxicity before chemotherapy administration and can allow dose adjustment .

It is secreted in the milk.Irinotecan can induce both early and late forms of diarrhea, which may be severe.Early diarrhea can be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping.

It is secreted in the milk.Irinotecan can induce both early and late forms of diarrhea, which may be severe.Early diarrhea can be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping.

It is secreted in the milk.Irinotecan can induce both early and late forms of diarrhea, which may be severe.Early diarrhea can be accompanied by cholinergic symptoms of rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping.

It depends on binding of a bleomycin/iron complex to DNA, which then reduces molecular oxygen to free oxygen radicals that cause primarily single strand breaks.Bleomycin sulfate <Blenoxane, Teva> is used in the treatment of Hodgkin and non-Hodgkin lymphoma as a component of the ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen, of squamous cell carcinoma, and of testicular cancer.

Cardiotoxicity can occur due to supraventricular arrhythmia .

However, the polyethylene glycol (PEG) in the formulation may cause hand-foot syndrome as an adverse effect29.Liposomal daunorubicin <DaunoXome> is a liposome encapsulated preparation with a diameter of 45 nm that is free of polyethylene glycol.

glycol (PEG) in the formulation may cause hand-foot syndrome as an adverse effect 29 .

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.Clofarabine triphosphate inhibits Ribonucleotide Reductase, leading to a depletion of the deoxyribonucleotide triphosphate (dNTP) pools.Clofarabine induces apoptosis through direct and indirect action on mitochondria by releasing Cytochrome c and other pro-apoptotic factors, including AIF (Apoptosis Inducing Factor), APAF-1 (Apoptotic Protease Activating Factor-1), and Caspase-9.The agent received accelerated approval from the U.S. FDA in 2004.

A ratio of clofarabine triphosphate to dATP < 1 results in the insertion of clofarabine monophosphate into the middle of the DNA structure and inhibits DNA repair.Clofarabine triphosphate inhibits Ribonucleotide Reductase, leading to a depletion of the deoxyribonucleotide triphosphate (dNTP) pools.Clofarabine induces apoptosis through direct and indirect action on mitochondria by releasing Cytochrome c and other pro-apoptotic factors, including AIF (Apoptosis Inducing Factor), APAF-1 (Apoptotic Protease Activating Factor-1), and Caspase-9.The agent received accelerated approval from the U.S. FDA in 2004.

Because aminosalicylate derivatives may inhibit the enzyme Thiopurine S-Methyltransferase (TPMT) they should be administered with caution to patients on 6-mercaptopurine therapy.The mercaptopurine derivative methylthioinosine (6-(methylmercapto)purine riboside, 6-MMPR) inhibits Amidophosphoribosyl Transferase, the first committed step in de novo purine synthesis, and inhibits cell proliferation induced by Fibroblast Growth Factor-2 (FGF-2).

Increases in the catabolism of 5-fluorouracil, mainly dependent on the rate limiting enzyme Dihydropyrimidine Dehydrogenase, can cause resistance to fluoropyrimidine based chemotherapy.

This is likely due to poorer activation of porfiromycin by DT-Diaphorase and a greater dependence of this drug on activation by NADPH : Cytochrome P450 Reductase compared with mitomycin C ( Begleiter 2000 ) .

Low doses of adozelesin , bizelesin , or carzelesin induce cell cycle arrest , high doses induce apoptosis .

thioTEPA is activated by CYP3A4 and CYP2D6.