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Temsirolimus (Fig. 10.27) is an esterified derivative of rap-amycin and in a similar manner binds initially to the protein FKBP-12(FK506-binding protein).159 This complex then acts to inhibit the mammalian target of rapamycin (mTOR), a serine-threonine kinase that plays a crucial role in cell division. It is somewhat unique in its method of ki-nase inhibition, because it actually binds to an allosteric modulator of the kinase rather than just binding to the ATP-binding site like most other kinase inhibitors. Binding of temsirolimus inhibits the phosphorylating activity of mTOR. As shown in Table 10.3, mTOR regulates the Akt/PKB pathway, and therefore, one way in which the agent acts is to inhibit this pathway. An additional mechanism involves the ability of mTOR to initiate protein synthesis independent of the Akt/PKB pathway. Blockade of mTOR results in inhibition of protein synthesis and prevents the cell from moving past the G1 phase into the

S phase. More specifically, mTOR is prevented from phos-phorylating 4E-binding protein-1(4E-BP1) an initiating factor and 40S ribosomal protein S6 kinase (p70S6 kinase), both of which are involved in initiating protein synthesis necessary for the cell cycle. In addition, mTOR is involved in the control of several growth factors such VEGF, PDGF, and TGF, which are involved in cell growth and angiogen-esis. Temsirolimus is available as a 25-mg/mL injection for IV administration in the treatment of advanced RCC. The agent is extensively metabolized and undergoes rapid hydrolysis of the ester function to give rapamycin that retains activity.160 Additional metabolism is mediated primarily by CYP3A4 to give several hydroxylated and demethylated metabolites that are inactive. The agent and metabolites are eliminated primarily in the feces with half-lives of 17 and 55 hours for temsirolimus and rapamycin, respectively. This agent, like rapamycin, possesses immunosuppressant properties and there is an increased risk of infection. The most serious side effects are interstitial lung disease, perforation of the bowel, and acute renal failure although these occur only rarely. The most commonly seen side

Bexarotene Estramustine

Figure 10.27 • Miscellaneous antineoplastic agents.

effects are rash, weakness, mucositis, nausea, edema, and anorexia.


Proteasomes normally function to degrade proteins that are no longer needed by the cell. Such proteins are normally marked by the addition of ubiquitin, a 76 amino acid protein that is added to the e-amino group of lysine residues on the target proteins. The marked proteins are then hy-drolyzed by the large barrel-shaped proteasomes to give peptides of 7 to 8 residues that may be further hydrolyzed and reutilized by the cell. This process serves to regulate protein levels within the cell, remove defective proteins, and becomes important in maintaining normal signal trans-duction. Inhibition of the proteasomes results in the build up of ubiquitylated proteins, which disrupts cell-signaling processes and cell growth (Fig. 10.28). The signaling by transcription factor NF-kB (nuclear factor kB) appears to be especially sensitive to bortezomib. NF-kB is associated with the transcription of antiapoptotic and proliferative genes but is under the control of IkB (inhibitor of NF-kB). IkB can itself be phosphorylated by IKK (IkB kinase), which marks IkB for ubiquitylation and destruction allowing NF-kB to mediate its antiapoptotic and proliferative ef fects. In the presence of the competitive inhibitor bortezomib (IC50 = 0.6 nM), the 26S proteasome is inhibited and the ubiquitylated IkB is still capable of inhibiting NF-kB, preventing its effects.161

The agent is used primarily in treating multiple myeloma, where NF-kB is thought to be especially important because of its regulation of VEGF and adhesion molecules, which play important roles in this cancer. The agent is also used in treating non-Hodgkin's lymphoma.

Bortezomib is available in 10-mL vials containing 3.5 mg that is administered intravenously for the treatment of multiple myeloma. The agent contains the unique boronic acid group, which serves as a bioisosteric replacement for an aldehyde functionality and forms a tetrahedral complex with a threonine hydroxyl group present on the proteasome. Several aldehydes were known to be protea-some inhibitors, but their incorporation resulted in racemi-zation of the a-carbon. The boronic acids were not susceptible to the same racemization, and stereochemistry was preserved in vivo giving maximal inhibition. The agent has a half-life of 9 to 15 hours with the major metabolizing enzymes being CYP3A4 and CYP2C19.162 Metabolism involves the oxidative removal of boron from the agent to give two diastereomeric carbinolamines. Both of the metabolites are inactive, the boronic acid functionality

Figure 10.28 • Actions of proteasomes on NF-kB.

being necessary for binding of the proteasome. The elimination of the agent has not been well characterized.

The major toxicities seen with the agent are generalized weakness, nausea, vomiting, diarrhea, peripheral neuropathy, fever, and orthostatic hypotension. Myelosuppression also occurs normally as thrombocytopenia and neutropenia.


Histones are proteins around which DNA is wound in the process of packing DNA into the nucleus. They also have a role in regulating the transcription of genes, and this is controlled by the covalent modifications acetylation, phos-phorylation, and methylation to which they are subject. The specific modifications present on the histones or his-tone code has been proposed to determine which transcription factors associate with specific genes and result in their replication.163 Acetylation occurs at the e-amino group of lysine and is accomplished by histone acetyltransferase enzymes, whereas deacetylation is accomplished by histone deacetylase enzymes. The result of inhibition of histone deacetylase is hyperacetylation of lysine residues of the hi-stone proteins. The positively charged e-amino groups of the lysine residues are believed to interact with the negatively charged phosphate backbone of DNA. Once acetyla-tion has occurred, this interaction is prevented, and the binding of transcription factors is favored. Therefore, the inhibition of deacetylation by vorinostat, a histone deacetylase inhibitor (HDACis), results in the increased transcription of certain genes. Specifically, this has been associated with upregulation of a regulatory protein known as p21, which serves to inhibit progression past the G1 phase of the cell cycle. Other genes and their proteins are also effected by vorionostat such as Hsp90 (heat shock protein 90) and BCL6.

Vorinostat fits the basic pharmacophore for the HDACis (Fig. 10.29), which consists of a hydrophobic cap region connected to a zinc coordinating functionality by a hy-drophobic linker.164 The hydroxamic acid functionality is capable of bidendate binding to zinc present in the enzyme and is a major factor in the overall binding of the compound. The compound inhibits HDAC1, 2, 3, and 6 classes of this enzyme with nanomolar (<86 nM) IC50 values.165

Cap Hydrophobic Zinc-binding eft

Figure 10.29 • Pharmacophore for histone deacetylase inhibitors.

The agent is given orally and is available in 100-mg capsules for the treatment of cutaneous T-cell lymphoma. The bioavailability is 43%, and the agent is 71% bound to plasma proteins. Extensive metabolism of the agent occurs to give the O-glucuronide of the hydroxamic acid function and 4-anilino-4-oxobutanoic acid with minimal involvement of isozymes of CYP. The metabolites, both of which are inactive, are eliminated in the urine and the drug has a terminal elimination half-life of 2 hours. The most commonly reported adverse effects are fatigue, diarrhea, and nausea. Elevations in glucose and triglyceride levels are commonly seen with the agent. The agent has been associated with thrombocytopenia, an increased risk of clotting resulting in pulmonary embolism and possibly prolongation of the QTc interval.


Arsenic trioxide is available in 10-mL vials for IV administration as second-line therapy in the treatment of acute promyelocytic leukemia (APL). The mechanism of the agent has not been well characterized; however, work has indicated that the agent may cause the degradation of a protein that blocks myeloid differentiation. Acute lymphocytic leukemia is associated with a translocation in which the promyelocytic leukemia (PML) gene is fused with the retinoic acid receptor gene (RARa), and the protein that results from this genetic rearrangement prevents myeloid dif-ferentiation.166 Arsenic trioxide is capable of degrading this protein and allowing the cells to differentiate. Additional effects have included stimulation of apoptosis by decreasing Bcl-2 activity and stimulation of caspase enzymes and p53. Angiogenesis is inhibited by the inhibition of VEGF at the protein level.167 The agent is widely distributed after IV administration; however, the pharmacokinetics of the agent have not been well characterized. Metabolism studies have shown that the agent undergoes reduction to trivalent arsenic followed by methylation to give monomethylarsonic and dimethylarsinic acids, which are eliminated in the urine. Unlike most other antineoplastic agents, myelosup-pression does not occur in fact many patients (50%-60%) experience leukocytosis in which white blood cell count increases. APL differentiation syndrome is seen in many patients (30%) and presents as fever, shortness of breath, weight gain, pulmonary infiltrates, and pleural or pericar-dial effusions. This may be fatal and is commonly treated with high-dose dexamethasone upon initial suspicion. The presentation of APL differentiation syndrome are identical for arsenic trioxide and retinoic acid. Additional adverse effects include fatigue, a prolonged QT interval, dizziness, mild hyperglycemia, and mild nausea and vomiting.


Tretinoin is available in 10-mg capsules for oral administration in the treatment of APL. The mechanism of action involves passive diffusion through the cell membrane and then movement to the nucleus where it interacts with the retinoic acid receptor (RAR) portion of the PML-RARa fusion protein. Binding of tretinoin allows the cell to differentiate and has also been shown to result in the destruction of the PML-RARa fusion protein. Resistance to tretinoin is problematic and associated with an increase in cellular retinoic acid-binding proteins (CRAPBs) located in the cy-tosol. The complexation with tretinoin prevents movement into the nucleus and may present the drug to metabolizing enzymes that inactivate it. Amino acid mutation of the PML-RARa protein has also been established as a mechanism of resistance. The agent is well absorbed upon oral administration and highly (95%) protein bound. Metabolism occurs in the liver and several inactive metabolites have been identified including 13-cis-retinoic acid, 4-oxo cis-retinoic, 4-oxo trans-retinoic acid and 4-oxo trans-retinoic acid glucuronide. Elimination occurs in the urine (63%) and feces (31%) with an elimination half-life of 40 to 120 minutes. Vitamin A toxicity is seen in nearly all patients and presents as headache, fever, dryness of the skin, skin rash, mucositis, and peripheral edema. APL differentiation syndrome such as that seen for arsenic trioxide also occurs. Cardiovascular effects include flushing, hypotension, CHF, stroke, and myocardial infarction have been reported but occur only rarely. There are also several CNS and GI effects that have been associated with the agent as well.


Bexarotene is available in 75-mg capsules for oral administration in the treatment of refractory cutaneous T-cell lymphoma. The agent is also available as a gel that may be used topically. The mechanism of action has not been fully established but is thought to involve binding to retinoid receptors resulting ultimately in the formation of transcription factors that promote cell differentiation and regulate cellular prolif-eration.168 Bexarotene has been demonstrated to activate apoptosis as a result of stimulation of caspase 3 and inhibition of survivin, an antiapoptotic protein that would normally inhibit caspase activity.169 Apoptosis is also stimulated because of cleavage of poly(ADP-Ribose) polymerase, which is antiapoptotic. Reduced expression of the retinoid receptor subtypes RXRa and RARa has also been demonstrated for the agent. Absorption is nearly complete after oral administration and plasma protein binding is high (<99%).170 There is extensive metabolism in the liver to give 6- and 7-hydroxy-bexarotene and 6- and 7-oxo-bexarotene as well as glucuronides of these metabolites and the parent. Elimination occurs via the feces with an elimination half-life of 7 hours. Adverse effects include hypercho-lesterolemia, hypertriglyceridemia, hypothyroidism, myelo-suppression, nausea, and skin rash.


Asparaginase is available in 10-mL vials for intramuscular and IV use in the treatment of acute lymphocytic leukemia.

Cap Hydrophobic Zinc-binding


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  • ruby stevenson
    What is miscellaneous pharmaceutical agents?
    2 years ago

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