thioTEPA is activated by CYP3A4 and CYP2D6 .

Whereas both cyclophosphamide and ifosfamide are activated by Cytochromes P450 2B1 and 2C6 / 2C11 , only ifosfamide is also activated by Cytochrome P450 3A .

thioTEPA is activated by CYP3A4 and CYP2D6.

thioTEPA is activated by CYP3A4 and CYP2D6 .

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

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 P53 pathway can partially mediate cisplatin cytotoxicity.

Drug resistance may be caused by platinum efflux, detoxification through thiols, apoptosis resistance, or enhanced DNA repair.MINOR GROOVE DNA BINDING ANTIBIOTICS (A/T RICH SITES)MINOR GROOVE DNA BINDING ANTIBIOTICS (G/C RICH SITES)) is a methylazirinopyrroloindoledioneFig.

The S phase specific induction of DNA damage responses by adozelesin depends on active reduplication forks.

Individuals with this condition may develop life threatening toxicity following exposure to 5-fluorouracil or capecitabine.Reduced anabolism of 5-fluorouracil to the nucleotide form can lead to drug resistance.

However, in cells lacking the tumor suppressor protein P21, bizelesin, as well as adozelesin, trigger apoptosis, reflecting a crucial role for P21 in sustained bizelesin induced G 2 /M arrest (Cao 2003) .

These DNA modifications lead to DNA fragmentation and cell death .

Drug resistance may be caused by platinum efflux , detoxification through thiols , apoptosis resistance , or enhanced DNA repair .

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

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

Molecularly Targeted Therapy The cells of glioblastomata and anaplastic gliomatas secrete glutamate and also express AMPA Glutamate Receptors , which contribute to proliferation , migration and neurotoxicity .

The cells of glioblastomata and anaplastic gliomatas secrete glutamate and also express AMPA Glutamate Receptors , which contribute to proliferation , migration and neurotoxicity .

Whereas both cyclophosphamide and ifosfamide are activated by Cytochromes P450 2B1 and 2C6/2C11, only ifosfamide is also activated by Cytochrome P450 3A.N-dechloroethylation of the parent drug yields mono-functional metabolites that have lost their DNA cross-linking activity and therapeutic efficacy.

Whereas both cyclophosphamide and ifosfamide are activated by Cytochromes P450 2B1 and 2C6/2C11, only ifosfamide is also activated by Cytochrome P450 3A.N-dechloroethylation of the parent drug yields mono-functional metabolites that have lost their DNA cross-linking activity and therapeutic efficacy.

Whereas both cyclophosphamide and ifosfamide are activated by Cytochromes P450 2B1 and 2C6/2C11, only ifosfamide is also activated by Cytochrome P450 3A.N-dechloroethylation of the parent drug yields mono-functional metabolites that have lost their DNA cross-linking activity and therapeutic efficacy.

The kinase PKB (Protein Kinase B, AKT) promotes cell survival and down-regulates apoptosis.

These events lead to apoptosis .

A common adverse effect of semustine is prolonged myelosuppression , which may result in infection and bleeding .

Adverse Effects A common adverse effect of semustine is prolonged myelosuppression , which may result in infection and bleeding .

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

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Steroid-coupled nitrogen mustards Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

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

The bone marrow depressant effects of uracil mustard may result in an increased incidence of microbial infections , delayed healing , and bleeding .

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

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

ThioTEPA causes amenorrhea and interferes with spermatogenesis.

ThioTEPA causes amenorrhea and interferes with spermatogenesis .

Thioguanine causes birth defects if taken during pregnancy .

Thioguanine causes birth defects if taken during pregnancy.Administration of a live vaccine can be dangerous during treatment with thioguanine.

Thioguanine causes birth defects if taken during pregnancy.

Streptozocin prolongs the elimination half-life of doxorubicin and thus can lead to severe bone marrow suppression.

When combined with ethanol, procarbazine can cause adverse drug reactions in some patients.

When combined with ethanol , procarbazine can cause adverse drug reactions in some patients .

A common adverse effect of semustine is prolonged myelosuppression , which may result in infection and bleeding .

Adverse Effects A common adverse effect of semustine is prolonged myelosuppression , which may result in infection and bleeding .

Clofarabine can produce systemic inflammatory response syndrome (SIRS) and capillary leak syndrome, manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure.

Clofarabine can produce systemic inflammatory response syndrome (SIRS) and capillary leak syndrome, manifested by the rapid development of tachypnea, tachycardia, hypo-47 The ENT transporters work bi-directionally, driven by the nucleoside concentration gradient between the inside and the outside of the cell membrane.

Clofarabine can produce systemic inflammatory response syndrome (SIRS) and capillary leak syndrome, manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, and multi-organ failure.

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.

As an alkylating agent , dimethylbusulfan induces neutropenia .

Adverse Effects As an alkylating agent , dimethylbusulfan induces neutropenia .

It has been under investigation as a second-line treatment for various cancers.As an alkylating agent, dimethylbusulfan induces neutropenia.Treosulfan (2,3-dihydroxybutane-1,4-diyl dimethanesulfonate) (NSC 39069) is the prodrug of a bifunctional sulfonate alkylating agent, which converts non-enzymatically via a monoepoxide intermediate to L-diepoxybutane.

It has been under investigation as a second-line treatment for various cancers.Adverse Effects As an alkylating agent, dimethylbusulfan induces neutropenia.Treosulfan (2,3-dihydroxybutane-1,4-diyl dimethanesulfonate) (NSC 39069) is the prodrug of a bifunctional sulfonate alkylating agent, which converts non-enzymatically via a monoepoxide intermediate to L-diepoxybutane.

It has been under investigation as a second-line treatment for various cancers.As an alkylating agent, dimethylbusulfan induces neutropenia.Treosulfan (2,3-dihydroxybutane-1,4-diyl dimethanesulfonate) (NSC 39069) is the prodrug of a bifunctional sulfonate alkylating agent, which converts non-enzymatically via a monoepoxide intermediate to L-diepoxybutane.

It has been under investigation as a second-line treatment for various cancers.Adverse Effects As an alkylating agent, dimethylbusulfan induces neutropenia.Treosulfan (2,3-dihydroxybutane-1,4-diyl dimethanesulfonate) (NSC 39069) is the prodrug of a bifunctional sulfonate alkylating agent, which converts non-enzymatically via a monoepoxide intermediate to L-diepoxybutane.

It has been under investigation as a second-line treatment for various cancers.As an alkylating agent, dimethylbusulfan induces neutropenia.Treosulfan (2,3-dihydroxybutane-1,4-diyl dimethanesulfonate) (NSC 39069) is the prodrug of a bifunctional sulfonate alkylating agent, which converts non-enzymatically via a monoepoxide intermediate to L-diepoxybutane.

It has been under investigation as a second-line treatment for various cancers.Adverse Effects As an alkylating agent, dimethylbusulfan induces neutropenia.Treosulfan (2,3-dihydroxybutane-1,4-diyl dimethanesulfonate) (NSC 39069) is the prodrug of a bifunctional sulfonate alkylating agent, which converts non-enzymatically via a monoepoxide intermediate to L-diepoxybutane.

Inosine dialdehyde (NSC 118994) <Inox> is a toxic purine analog that inhibits Ribonucleotide Reductase, resulting in the decreased synthesis of DNA, RNA, and proteins, and leading to cell cycle arrest at the G2/M transition.

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.

Ifosfamide produces less myelotoxicity (mainly leukopenia) than cyclophosphamide and also exhibits little cross-resistance.

The metabolic ifosfamide product acrolein can contribute to the hemorrhagic cystitis associated with oxazaphosphorine therapy.

Polycyclic aromatic antibiotics ( anthracyclins , anthracenediones , anthrapyrazoles ) and enediynes generate free radicals through redox cycling by a mechanism that depends in part 24 The suffix - mycin is conventionally used to describe a substance derived from a bacterium in the order Actinomycetales .

Due to its mechanisms of action through genetic damage, etoposide may increase the risk of developing leukemia.

O-demethylation of the etoposide dimethoxyphenol ring occurs through the CYP450 3A4 pathway to produce the corresponding catechol.

It is caused by drug metabolites that agonize AMPA / Kainate Receptors and induce cellular acidification in cortical neurons .

Iron mediated free radical reactions enable anthracyclines to produce formaldehyde ( HCHO ) from carbon cellular sources like spermine and lipids .

5-fluorouracil causes myelosuppression .

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

Hydroxyurea selectively inhibits Ribonucleoside Diphosphate Reductase, an enzyme required to convert ribonucleoside diphosphates into deoxyribonucleoside diphosphates45.

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.

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.

The long-term circulation of the PEGylated daunorubicin allows protracted extravasation and underlies this form of handfoot syndrome.

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

Unlike other common alkylating agents, cyclophosphamide can occasionally induce remission in acute childhood leukemias, and it can be used to prolong remission.

Alopecia caused by cyclophosphamide is common, but usually temporary despite continued administration of the drug.

Unlike other common alkylating agents , cyclophosphamide can occasionally induce remission in acute childhood leukemias , and it can be used to prolong remission .

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

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

-Clofarabine triphosphate inhibits Ribonucleotide Reductase, leading to a depletion of the deoxyribonucleotide triphosphate (dNTP) pools.

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 drug is converted intracellularly to the active metabolites difluorodeoxycytidine di-and triphosphate (dFdCDP and dFdCTP).-dFdCDP inhibits Ribonucleotide Reductase 44 , thereby decreasing the deoxynucleotide pool available for DNA synthesis -dFdCTP is incorporated into DNA, resulting in DNA strand termination and apoptosis.After incorporation into DNA, gemcitabine has a prolonged intracellular half-life.

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

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.

The pathway synthesizes inosine monophosphate from ribose-5-phosphate , the ribonucleotide of hypoxanthine and the first nucleotide formed during the synthesis of purine .

Rapid infusion of carmustine may produce intensive flushing of the skin and suffusion of the conjunctiva within 2 h, lasting about 4 h.

Drug resistance may be caused by platinum efflux, detoxification through thiols, apoptosis resistance, or enhanced DNA repair.MINOR GROOVE DNA BINDING ANTIBIOTICS (A/T RICH SITES)MINOR GROOVE DNA BINDING ANTIBIOTICS (G/C RICH SITES)) is a methylazirinopyrroloindoledioneFig.

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Steroid-coupled nitrogen mustards Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Steroid-coupled nitrogen mustards Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

Carboplatin causes thrombocytopenia with a nadir of 10–14 days.

Carboplatin causes thrombocytopenia with a nadir of 10-14 days .

Carboplatin also leads to alopecia, fatigue, and abnormal blood electrolyte levels (magnesium, sodium, potassium, calcium).

Carboplatin also leads to alopecia , fatigue , and abnormal blood electrolyte levels ( magnesium , sodium , potassium , calcium ) .

Carboplatin also leads to alopecia, fatigue, and abnormal blood electrolyte levels (magnesium, sodium, potassium, calcium).

Carboplatin also leads to alopecia , fatigue , and abnormal blood electrolyte levels ( magnesium , sodium , potassium , calcium ) .

Allopurinol may be preferred to prevent or reverse uracil mustard induced hyperuricemia and the risk of uric acid nephropathy.Estramustine phosphate sodium (estradiol 3-[bis(2-chloroethyl)carbamate] 17-(dihydrogen phosphate), disodium salt, monohydrate) <Emcyt> is an orally available synthetic drug that combines estradiol and mechlorethamine through a carbamate link.

Oligomenorrhea or azoospermia can be induced by mechlorethamine and may not recover for years after termination of therapy.

The vasoconstrictor epinephrine in the gel enhances the penetration of methotrexate into the tumor tissue and reduces the dispersion to the surrounding tissues, thereby increasing the local concentration of methotrexate and improving its anti-tumor activity.

Within this subgroup, differences in structure from the parent compound aminopterin are shaded in pink The vasoconstrictor epinephrine in the gel enhances the penetration of methotrexate into the tumor tissue and reduces the dispersion to the surrounding tissues, thereby increasing the local concentration of methotrexate and improving its anti-tumor activity.

In chronic granulocytic leukemia, busulfan can induce remission in 90 % of patients after the initial course of therapy.

In chronic granulocytic leukemia , busulfan can induce remission in 90 % of patients after the initial course of therapy .

The wafers produce high local concentrations of carmustine for several weeks directly into the tumor bed after surgery when the tumor burden is low.Molecularly Targeted Therapy The cells of glioblastomata and anaplastic gliomatas secrete glutamate and also express AMPA Glutamate Receptors, which contribute to proliferation, migration and neurotoxicity.

The wafers produce high local concentrations of carmustine for several weeks directly into the tumor bed after surgery when the tumor burden is low.The cells of glioblastomata and anaplastic gliomatas secrete glutamate and also express AMPA Glutamate Receptors, which contribute to proliferation, migration and neurotoxicity.

Like many other genotoxic agents, doxorubicin activates the binding of P53 to DNA, likely inducing apoptosis in this manner.

The combination of doxorubicin with cyclophosphamide causes a dramatic increase in the risk of secondary malignancies, most often acute myelomonocytic leukemia.Idarubicin <Idamycin, Idamycin PFS> is a semi-synthetic anthracycline derived from daunorubicin.

The combination of doxorubicin with cyclophosphamide causes a dramatic increase in the risk of secondary malignancies, most often acute myelomonocytic leukemia.Idamycin PFS> is a semi-synthetic anthracycline derived from daunorubicin.

An elevated activity of PKB associated pathways protects cells from apoptotic death induced by cisplatin.

Nuclear c-ABL activity can be stimulated by cisplatin and acts to transmit DNA damage signals.

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) .

Because c-ABL tyrosine kinase has a role in cisplatin mediated activation of apoptosis, a reduction in its activity can confer cisplatin resistance.

The metabolite chloroacetaldehyde may lead to the formation of chloroacetic acid and then to S-carboxymethylcysteine (SCMC) after conjugation with the amino acid cysteine.

- Actinomycin D causes single strand DNA breaks , possibly via a free radical intermediate or an interaction with Topoisomerase 2 .

Interactions between daunorubicin and metallic Cu II ions abundant in skin tissue generate reactive oxygen species, which stimulate Chemokine secretion from keratinocytes and result in inflammation.

The drug is Pregnancy Category D.Concurrent administration of hexamethylmelamine and antidepressants of the MAO inhibitor class can cause severe orthostatic hypotension.

The drug is Pregnancy Category D.Drug Interactions Concurrent administration of hexamethylmelamine and antidepressants of the MAO inhibitor class can cause severe orthostatic hypotension.

It is caused by drug metabolites that agonize AMPA/Kainate Receptors and induce cellular acidification in cortical neurons.

Whereas both cyclophosphamide and ifosfamide are activated by Cytochromes P450 2B1 and 2C6/2C11, only ifosfamide is also activated by Cytochrome P450 3A.N-dechloroethylation of the parent drug yields mono-functional metabolites that have lost their DNA cross-linking activity and therapeutic efficacy.

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

The drug is Pregnancy Category D.As a natural product, bleomycin may be the cause of anaphylactic reactions, immediate or delayed for several hours.

As a natural product, bleomycin may be the cause of anaphylactic reactions, immediate or delayed for several hours.

Vitamin C supplements can increase the adverse effects of methotrexate.

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

Iron mediated free radical reactions enable anthracyclines to produce formaldehyde (HCHO) from carbon cellular sources like spermine and lipids.

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

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.

ethyl)mitomycin C) (KT6149) is a semi-synthetic, water soluble disulfide derivative of mitomycin C. Activated by blood components and Glutathione, KW-2149 causes inter-strand DNA cross-links and DNA-protein The quinone of mitomycin C is reduced, altering the azinidine group to be opened and set up a conjugated system to a susceptible carbon.

However, it has limited clinical usefulness because of its rapid inactivation by Adenosine Deaminase.A product of the fermentation by Streptomyces antibioticus is 2′-deoxycoformycin (co-vidarabine, dCF) (NSC-218321, CL-825) <Premarin, Pentostatin, Nipent>.

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

Folinic acid can enhance the toxicity of 5-fluorouracil; in elderly patients, deaths from severe enterocolitis, diarrhea, and dehydration can result.

Ceramide formation occurs after reactive oxygen activation of Neutral Sphingomyelinase.

Anthracycline-formaldehyde conjugates intercalate into DNA by covalent bonding of the Schiff base with the 2-amino group of a G in the minor groove of the DNA (Taatjes et al. 1997 ).-Ceramide formation occurs after reactive oxygen activation of Neutral Sphingomyelinase.

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.

The metabolic ifosfamide product acrolein can contribute to the hemorrhagic cystitis associated with oxazaphosphorine therapy.

The metabolic ifosfamide product acrolein can contribute to the hemorrhagic cystitis associated with oxazaphosphorine therapy.

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 .

Valrubicin causes DNA damage, inhibits Topoisomerase 2, and leads to cell cycle arrest in G2.

Valrubicin causes DNA damage, inhibits Topoisomerase 2, and leads to cell cycle arrest in G2.

Thereby exatecan inhibits DNA reduplication and triggers apoptotic cell death.

Thereby exatecan inhibits DNA reduplication and triggers apoptotic cell death .

The repair of the irofulven induced DNA damage is dependent on functioning DNA Helicases (the double helical configuration, in which DNA strands naturally reside, requires their separation by Helicases for transcription or reduplication).

Fotemustine may cause retinal atrophy or retinal detachment .

50-60 % of the dose administered is excreted in the urine, 5 % in the feces.Adverse Effects Fotemustine may cause retinal atrophy or retinal detachment.

50-60 % of the dose administered is excreted in the urine, 5 % in the feces.Adverse Effects Fotemustine may cause retinal atrophy or retinal detachment.

IL-1beta secretion was not affected by treatment with the NLRP3 inhibitor glyburide XREF_BIBR or parthenolide, which has also been shown to inhibit NLRP3 XREF_BIBR.

Glyburide and parthenolide both inhibited NLRP3 activation by LPS and ATP (data not shown).

XREF_BIBR have shown that parthenolide directly inhibits caspase-1 by alkylation of certain cysteine residues.

However, the previous study xref did not test AIM2 activation so perhaps parthenolide only inhibits caspase-1 in response to NLRP3 or NLRC4 activation.

Our results disagree with this assertion as we did not find that parthenolide inhibited caspase-1 in response to AIM2 stimulation.

Water activated by atomic oxygen on Au (111) to oxidize CO at low temperatures.

Neonatal mice deficient in TLR4 have decreased LGR5+ stem cell proliferation and crypt fission compared to wild type mice.

Neonatal mice deficient in TLR4 have markedly diminished LGR5+ stem cell proliferation and diminished crypt fission.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE₂ production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

In contrast, TLR4 activation by LMW-HA requires a TLR4 and MD2 complex but is independent of CD14 and LPS binding protein.

TLR4 activation by LPS requires a TLR4 and MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4 and MD2 complex.

In contrast, TLR4 activation by LMW-HA requires a TLR4-MD2 complex but is independent of CD14 and LPS binding protein.

TLR4 activation by LPS requires a TLR4-MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4-MD2 complex ( xref , xref ).

This may be the product of endogenous HAs of different molecular weights binding separately to CD44 and TLR4 or it may be the product of HA binding to a CD44 and TLR4 complex.

There is evidence that LMW-HA binds both CD44 and TLR4.

This may be the product of endogenous HAs of different molecular weights binding separately to CD44 and TLR4 or it may be the product of HA binding to a CD44-TLR4 complex ( xref , xref ).

This suggests that endogenous HA binding to both CD44 and TLR4 promotes intestinal growth.

Hyaluronic acid binding to TLR4 in pericryptal macrophages results in cyclooxygenase2- dependent PGE 2 production, which transactivates EGFR in LGR5+ crypt epithelial stem cells leading to increased proliferation.

Although most studies suggest that HMW-HA binds CD44 and LMW-HA binds TLR2 and TLR4.

TLR2 and TLR4 binding to LMW-HA promotes the production of proinflammatory cytokines including TNFα, MIP, IL-1β, IL-6, and IL-12 ( xref , xref – xref ).

TLR2 and TLR4 preferentially bind to LMW-HA.

Among the PAMPs are lipoteichoic acid (LTA), a component of gram positive bacteria that binds TLR2, and LPS, a component of gram negative bacteria that binds TLR4.

This review addresses two novel related intercellular pathways in which a host molecule, HA, binding to TLR2 and TLR4 drives physiologic processes in the intestine and colon.

This suggests that endogenous HA binding to TLR2 and TLR4 blocks bleomycin-induced apoptosis.

PGE₂ binding to EP2 blocks radiation-induced apoptosis by an AKT-EGFR mechanism ( xref ).

Although both LMW-HA and LPS bind to TLR4, the results of TLR4 activation by LMW-HA and LPS are not identical.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

HA binds to CD44, TLR2, TLR4, the receptor for HA mediated motility (RHAMM), layilin, lymphatic vessel endothelial HA receptor- 1 (LYVE-1), and HA receptor for endocytosis.

Low dose, high MW endogenous HA binding to TLR4 may preferentially promote PGE2 production, whereas high dose low MW exogenous HA or LPS or LTA binding to TLR4 may preferentially promote CXCL12 production.

EGFR can activate β-catenin via the receptor tyrosine kinase-PI3K-Akt pathway ( xref ).

EGFR can activate beta-catenin via the receptor tyrosine kinase-PI3K-Akt pathway.

Although the evidence suggests that EGFR activation in response to TLR4 signaling is mediated by PGE2, it is also possible that TLR4 signaling promotes EGFR activation through the production of amphiregulin, epiregulin or other EGFR ligands.

Administration of exogenous TLR2 or TLR4 agonists activates TLR2 and TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2 expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells.

This suggests that TLR2 and TLR4 signaling driven by PAMPs from commensal bacteria promotes epithelial proliferation during wound repair in the colon.

In contrast to wound repair, where inflammation accompanies enhanced epithelial proliferation driven by TLR2 and TLR4 activation, in intestinal growth TLR4 activation promotes epithelial proliferation in the absence of inflammation.

In contrast , in adult mice TLR2 / TLR4 activation on pericryptal macrophages by exogenous HA or other TLR2 / TLR4 agonists results in CXCL12 production resulting in the migration of COX-2 expressing MSCs .

Administration of exogenous TLR2 or TLR4 agonists activates TLR2 and TLR4 on pericryptal macrophages inducing CXCL12 production with migration of cyclooxygenase2 expressing mesenchymal stem cells from the lamina propria of the villi to a site adjacent to LGR5+ epithelial stem cells.

TLR4 activation by LPS requires a TLR4 and MD2 complex, LPS binding protein, and CD14 which delivers LPS to the TLR4 and MD2 complex.

TLR4 activation by LPS and LMW-HA require different accessory molecules.

Although both LMW-HA and LPS bind to TLR4, the results of TLR4 activation by LMW-HA and LPS are not identical.

In human biliary carcinoma cells in vitro, addition of LPS initiates a positive feedback loop of TLR4 activation, PGE2 production through COX-2 and EGFR activation.

TLR4 activation by LPS requires a TLR4-MD2 complex , LPS binding protein , and CD14 which delivers LPS to the TLR4-MD2 complex ( 33 , 34 ) .

TLR4 activation by LPS and LMW-HA require different accessory molecules .

Although both LMW-HA and LPS bind to TLR4 , the results of TLR4 activation by LMW-HA and LPS are not identical .

Activation of TLR2 by LTA or activation of TLR4 by LPS or HA results in the release of the chemokine CXCL12 , which binds to CXCR4 on COX-2 expressing MSCs .

In this pathway, TLR4, which is usually associated with innate immunity, is activated not by the microbial product LPS, but by HA, a host molecule.

Although there are differences in the accessory molecules involved in TLR4 activation by LPS and LMW - HA , TLR4 activation by either one promotes wound healing ( 12 , 27 , 28 , 33 ) .

In mice deficient in TLR4, PEP-1 does not further reduce LGR5+ stem cell proliferation or crypt fission suggesting that TLR4 activation by endogenous HA drives LGR5+ stem cell proliferation and crypt fission.

TLR4 activation by HA drives LGR5+ epithelial stem cell proliferation and crypt fission in normal growth in the intestine and colon ( xref , xref ).

A study of pulmonary injury induced by intratracheal bleomycin demonstrates the role of HA activation of TLR4 in sterile injury ( xref ).

Although there are differences in the accessory molecules involved in TLR4 activation by LPS and LMW- HA, TLR4 activation by either one promotes wound healing ( xref , xref , xref , xref ).

TLR4 activation by HA also affects the immune response in ischemia- reperfusion injury in the kidney and in acute allograft rejection in a skin transplant model ( xref ).

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

TLR4 activation by HA also plays a role in wound repair.

Despite these suggestions there is good evidence that endogenous HA activates TLR4 and promotes growth even though most of the endogenous HA is in the high MW form.

There are suggestions that TLR4 is preferentially activated by the low MW form of HA.

TLR4 activation by HA drives LGR5+ epithelial stem cell proliferation and crypt fission in normal growth in the intestine and colon.

The presence of CD44 also enhances the effects of HA binding to TLR4 although the presence of CD44 is not required for HA activation of TLR4.

In the first pathway (XREF_FIG), intestinal and colonic growth is regulated by endogenous HA activating TLR4 on pericryptal macrophages resulting in the release of PGE2 which promotes LGR5+ stem cell proliferation, crypt fission and intestinal elongation.