| antimetabolites | The antimetabolites are structurally similar to endogenous compounds and are antagonists of folic acid (methotrexate), purines (mercaptopurine, thioguanine), or pyrimidines (fluorouracil, cytarabine, gemcitabine). Antimetabolites are CCS drugs acting primarily in the S phase of the cell cycle. In addition to their cytotoxic effects on neoplastic cells, the antimetabolites also have immunosuppressant actions |
| methotrexate mechanism of action and resistance | Methotrexate is an inhibitor of dihydrofolate reductase. It undergoes reduction to FH4 via a reaction catalyzed by intracellular nicotinamide-adenine dinucleotide phosphate–dependent DHFR. MTX enters the cell by active-transport processes that normally mediate the entry of N5-methyl-FH4. At high concentrations, the drug can also diffuse into the cell. MTX has an unusually strong affinity for DHFR and effectively inhibits the enzyme. Like tetra hydrofolate itself, MTX becomes polyglutamated within the cell, a process that favors intracellular retention of the compound due to increased negative charge. MTX polyglutamates also potently inhibit DHFR. his inhibition deprives the cell of folate coenzymes and leads to decreased production of compounds that depend on these coenzymes for their biosynthesis. Although these molecules include the nucleotides adenine, guanine, and thymidine and the amino acids methionine and serine, depletion of thymidine is the most prominent effect. This leads to depressed DNA, RNA, and protein synthesis and, ultimately, to cell death The inhibition of DHFR can only be reversed by a thousandfold excess of the natural substrate, dihydrofolate or by administration of leucovorin, which bypasses the blocked enzyme and replenishes the folate pool. [Note: Leucovorin, or folinic acid, is the N5-formyl group–carrying form of FH4.] MTX is specific for the S phase of the cell cycle. |
| methotrexate resistance | Decreased levels of the MTX polyglutamate have been reported in resistant cells and may be due to its decreased formation or increased breakdown. Resistance in neoplastic cells can be due to amplification (production of additional copies) of the gene that codes for DHFR, resulting in increased levels of this enzyme. The enzyme affinity for MTX may also be diminished. Resistance can also occur from a reduced influx of MTX, apparently caused by a change in the carrier-mediated transport responsible for pumping the drug into the cell. |
| mmethotrexate pharmcokinetics | Oral and intravenous administration of methotrexate affords good tissue distribution except to the CNS. Methotrexate is not metabolized, and its clearance is dependent on renal function. Adequate hydration is needed to prevent crystallization in renal tubules.it can also be administered by intramuscular, intravenous (IV), and intrathecal routes |
| methotrexate clinical use | Methotrexate is effective in choriocarcinoma, acute leukemias, non-Hodgkin’s and primary central nervous system lymphomas, and a number of solid tumors,burkitt lymphoma including breast cancer, head and neck cancer, and bladder cancer. Methotrexate is used also in rheumatoid arthritis psoriasis and ectopic pregnancy. In addition, low-dose MTX is effective as a single agent against certain inflammatory diseases, such as severe psoriasis and rheumatoid arthritis as well as Crohn disease. All patients receiving MTX require close monitoring for possible toxic effects. |
| mtx toxicity high dose | High doses of MTX undergo hydroxylation at the 7 position and become 7 hyroxymethotrexate. This derivative is much less active as an antimetabolite. It is less water soluble than MTX and may lead to crystalluria. Therefore, it is important to keep the urine alkaline and the patient well hydrated to avoid renal toxicity. Excretion of the parent drug and the 7-OH metabolite occurs primarily via urine, although some of the drug and its metabolite appear in feces due to enterohepatic excretion. |
| common toxicity mtx | a. Commonly observed toxicities: In addition to nausea, vomiting, and diarrhea, the most frequent toxicities occur in tissues that are constantly renewing. Thus, MTX causes stomatitis, myelosuppression, erythema, rash, urticaria, and alopecia. |
| leucovirin rescue | Some of these adverse effects can be prevented or reversed by administering leucovorin , which is taken up more readily by normal cells than by tumor cells. Doses of leucovorin must be kept minimal to avoid possible interference with the antitumor action of MTX. The toxic effects of methotrexate on normal cells may be reduced by administration of folinic acid (leucovorin); this strategy is called leucovorin rescue. Long-term use of methotrexate has led to hepatotoxicity and to pulmonary infiltrates and fibrosis. |
| renal damage mtx | Although uncommon during conventional therapy, renal damage is a complication of high-dose MTX and its 7-OH metabolite, which can precipitate in the tubules. Alkalinization of the urine and hydration help to prevent this problem. |
| hepatic function mtx | Hepatic function should be monitored. Longterm use of MTX may lead to cirrhosis. |
| pulmonary toxicity mtx | This is a rare complication. Children who are being maintained on MTX may develop cough, dyspnea, fever, and cyanosis. Infiltrates are seen on radiographs. This toxicity is reversible with suspension of the drug. |
| neurological toxicity mtx | These are associated with intrathecal administration of MTX and include subacute meningeal irritation, stiff neck, headache, and fever. Rarely, seizures, encephalopathy, or paraplegia occur. Long-lasting effects, such as learning disabilities, have been seen in children who received the drug by this route. |
| contraindication mtx | Because MTX is teratogenic in experimental animals and is an abortifacient, it should be avoided in pregnancy. [Note: MTX is used with misoprostol to induce abortion.] |
| Mercaptopurine (6-MP) and Thioguanine (6-TG) moa | Mercaptopurine and thioguanine are purine antimetabolites. Both drugs are activated by hypoxanthine-guanine phosphoribosyltransferases (HGPRTases) to toxic nucleotides that inhibit several enzymes involved in purine metabolism. Resistant tumor cells have a decreased activity of HGPRTase, or they may increase their production of alkaline phosphatases that inactivate the toxic nucleotides. 6-Mercaptopurine (6-MP) is the thiol analog of hypoxanthine. 6-MP and 6-thioguanine were the first purine analogs to prove beneficial for treating neoplastic disease. [Note: Azathioprine, an immunosuppressant, exerts its cytotoxic effects after conversion to 6-MP.] 6-MP is used principally in the maintenance of remission in acute lymphoblastic leukemia. 6-MP and its analog, azathioprine, are also beneficial in the treatment of Crohn disease. |
| Mercaptopurine (6-MP) and Thioguanine (6-TG) nucleotide formation | To exert its antileukemic effect, 6-MP must penetrate target cells and be converted to the nucleotide analog, 6-MP-ribose phosphate (better known as 6-thioinosinic acid, or TIMP). The addition of the ribose phosphate is catalyzed by the salvage pathway enzyme, hypoxanthineguanine phosphoribosyl transferase (HGPRT). |
| Mercaptopurine (6-MP) and Thioguanine (6-TG) inhibition of purine synthesis | A number of metabolic processes involving purine biosynthesis and interconversions are affected by the nucleotide analog, TIMP. Like adenosine monophosphate (AMP), guanosine monophosphate (GMP), and inosine monophosphate (IMP), TIMP can inhibit the first step of de novo purine-ring biosynthesis (catalyzed by glutamine phosphoribosyl pyrophosphate amidotransferase). TIMP also blocks the formation of AMP and xanthinuric acid from inosinic acid. Incorporation into nucleic acids: TIMP is converted to thioguanine monophosphate (TGMP), which after phosphorylation to di- and triphosphates can be incorporated into RNA. The deoxyribonucleotide analogs that are also formed are incorporated into DNA. This results in nonfunctional RNA and DNA. |
| Mercaptopurine (6-MP) and Thioguanine (6-TG) pharma | Mercaptopurine and thioguanine have low oral bioavailability because of first-pass metabolism by hepatic enzymes. The metabolism of 6-MP by xanthine oxidase is inhibited by the xanthine oxidase inhibitors allopurinol and febuxostat. Absorption by the oral route is erratic and incomplete. Once it enters the blood circulation, the drug is widely distributed throughout the body, except for the cerebrospinal fluid. The bioavailability of 6-MP can be reduced by the first-pass metabolism in the liver. While undergoing metabolism in the liver, 6-MP is converted to the 6-methylmercaptopurine derivative or to thiouric acid (an inactive metabolite). [Note: The latter reaction is catalyzed by xanthine oxidase.5] Because the xanthine oxidase inhibitor, allopurinol, is frequently used to reduce hyperuricemia in cancer patients receiving chemotherapy, it is important to decrease the dose of 6-MP by 75 percent in these individuals to avoid accumulation of the drug and exacerbation of toxicities. The parent drug and its metabolites are excreted by the kidney. |
| Mercaptopurine (6-MP) and Thioguanine (6-TG) resistance | Resistance is associated with 1) an inability to biotransform 6-MP to the corresponding nucleotide because of decreased levels of HGPRT (for example, in Lesch-Nyhan syndrome, in which patients lack this enzyme), 2) increased dephosphorylation, or 3) increased metabolism of the drug to thiouric acid or other metabolites. |
| Mercaptopurine (6-MP) and Thioguanine (6-TG) clinical use | Purine antimetabolites are used mainly in the acute leukemias and chronic myelocytic leukemia. |
| Mercaptopurine (6-MP) and Thioguanine (6-TG) toxicity | Bone marrow suppression is dose limiting, but hepatic dysfunction (cholestasis, jaundice, necrosis) also occurs. Side effects also include anorexia, nausea, vomiting, and diarrhea. Occurrence of hepatotoxicity in the form of jaundice has been reported in about one third of adult patients. |
| Fluorouracil (5-FU) mechanisms | Fluorouracil is converted in cells to 5-fluoro-2′-deoxyuridine-5′-monophosphate (5-FdUMP), which inhibits thymidylate synthase and leads to “thymineless death” of cells. Incorporation of FdUMP into DNA inhibits DNA synthesis and function while incorporation of 5-fluorouridine-5′-triphosphate (FUTP), another 5-FU metabolite, into RNA interferes with RNA processing and function. Tumor cell resistance mechanisms include decreased activation of 5-FU, increased thymidylate synthase activity, and reduced drug sensitivity of this enzyme.5-Fluorouracil (5-FU), a pyrimidine analog, has a stable fluorine atom in place of a hydrogen atom at position 5 of the uracil ring. The fluorine interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of thymidine, one of the essential precursors for DNA synthesis.It enters the cell through a carrier-mediated transport system and is converted to the corresponding deoxynucleotide (5-flurodeoxyuridine monophosphate [5-FdUMP];, which competes with deoxyuridine monophosphate for thymidylate synthase.7 5-FdUMP acts as a pseudosubstrate and is trapped with the enzyme and its coenzyme N5,N10-methylene tetrahydrofolic acid (leucovorin), in a ternary complex that cannot proceed to release products. DNA synthesis decreases due to lack of thymidine, leading to imbalanced cell growth and “thymidine-less death” of rapidly dividing cells. [Note: Leucovorin is administered with 5-FU, because the reduced folate coenzyme is required in the thymidylate synthase inhibition. Addition of the coenzyme increases the effectiveness of 5-FU to form a ternary complex and produce an anti pyrimidine effect. For example, the standard regimen for advanced colorectal cancer today is irinotecan plus 5-FU/leucovorin.] 5-FU is also incorporated into RNA, and low levels have been detected in DNA. In the latter case, a glycosylase excises the 5-FU, damaging the DNA. 5-FU produces the anticancer eff ect in the S phase of the cell cycle. |
| pharma fluorouracil | When given intravenously, fluorouracil is widely distributed, including into the cerebrospinal fluid. Elimination is mainly by metabolism.Because of its severe toxicity to the GI tract, 5-FU is given IV or, in the case of skin cancer, topically The drug penetrates well into all tissues, including the CNS. 5-FU is rapidly metabolized in the liver, lung, and kidney. It is eventually converted to fluoro-β-alanine, which is removed in the urine, and to CO2, which is exhaled. The dose of 5-FU must be adjusted in the case of impaired hepatic function. Increased rate of 5-FU catabolism through elevated levels of dihydropyrimidine dehydrogenase (DPD) can decrease the bioavailability of 5-FU. The DPD level varies from individual to individual and may differ by as much as sixfold in the general population. Knowledge about an individual’s DPD activity should allow more appropriate dosing of 5-FU . |
| clinical use fluorouracil | Fluorouracil is used in bladder, breast, colon, anal, head and neck, liver, and ovarian cancers. The drug can be used topically for keratoses and superficial basal cell carcinoma. 5-FU is employed primarily in the treatment of slowly growing solid tumors (for example, colorectal, breast, ovarian, pancreatic, and gastric carcinomas). When applied topically, 5-FU is also effective for the treatment of superficial basal cell carcinomas. 5-FU per se is devoid of antineoplastic activity. |
| resistance fluorouracil | Resistance is encountered when the cells have lost their ability to convert 5-FU into its active form (5-FdUMP) or when they have altered or increased thymidylate synthase levels. |
| toxicity fluorouracil | Gastrointestinal distress, myelosuppression, and alopecia are common.In addition to nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and GI mucosa, bone marrow depression (with bolus injection), and anorexia are frequently encountered. An allopurinol mouthwash has been shown to reduce (erythematous desquamation of the palms and soles) called the “hand-foot syndrome” is seen after extended infusions. |
| Cytarabine (ARA-C) moa and resistance | Cytarabine (cytosine arabinoside) is a pyrimidine antimetabolite. The drug is activated by kinases to AraCTP, an inhibitor of DNA polymerases. Of all the antimetabolites, cytarabine is the most specific for the S phase of the cell cycle. Resistance to cytarabine can occur as a result of its decreased uptake or its decreased conversion to AraCTP. is an analog of 2’-deoxycytidine in which the natural ribose residue is replaced by D-arabinose. Ara-C acts as a pyrimidine antagonist. The major clinical use of ara-C is in acute nonlymphocytic (myelogenous) leukemia in combination with 6-TG and daunorubicin.Ara-C enters the cell by a carrier-mediated process and, like the other purine and pyrimidine antagonists, must be sequentially phosphorylated by deoxycytidine kinase and other nucleotide kinases to the nucleotide form (cytosine arabinoside triphosphate, or ara-CTP ) to be cytotoxic. Ara-CTP is an effective inhibitor of DNA polymerase. The nucleotide is also incorporated into nuclear DNA and can retard chain elongation. It is, therefore,S-phase (and, hence, cell-cycle) specific. |
| Cytarabine (ARA-C) resistance | Resistance to ara-C may result from a defect in the transport process, a change in phosphorylating enzymes activity (especially deoxycytidine kinase), or an increased pool of the natural dCTP nucleotide. Increased deamination of the drug to uracil arabinoside(ara-U) can also cause resistance. |
| Cytarabine (ARA-C) pharma | Ara-C is not effective when given orally, because of its deamination to the noncytotoxic ara-U by cytidine deaminase in the intestinal mucosa and liver. Given IV, it distributes throughout the body but does not penetrate the CNS in sufficient amounts to be effective against meningeal leukemia. However, it may be injected intrathecally. A new preparation that provides slow release into the CSF is also available. Ara-C undergoes extensive oxidative deamination in the body to ara-U, a pharmacologically inactive metabolite. Both ara-C and ara-U are excreted in urine. |
| Cytarabine (ARA-C) adverse effects | Nausea, vomiting, diarrhea, and severe myelosuppression (primarily granulocytopenia) are the major toxicities associated with ara-C. Hepatic dysfunction is also occasionally encountered. At high doses or with intrathecal injection, ara-C may cause leukoencephalopathy or paralysis. |
| Gemcitabine mechanisms | Gemcitabine is a deoxycytidine analog that is converted into the active diphosphate and triphosphate nucleotide form. Gemcitabine diphosphate appears to inhibit ribonucleotide reductase and thereby diminish the pool of deoxyribonucleoside triphosphates required for DNA synthesis. Gemcitabine triphosphate can be incorporated into DNA, where it causes chain termination. Gemcitabine is a substrate for deoxycytidine kinase, which phosphorylates the drug to 2’,2’-difluorodeoxycytidine triphosphate. The latter compound inhibits DNA synthesis by being incorporated into sites in the growing strand that ordinarily would contain cytosine. Evidence suggests that DNA repair does not readily occur. Levels of the natural nucleotide, dCTP, are lowered, because gemcitabine competes with the normal nucleoside substrate for deoxycytidine kinase. Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for the generation of the deoxynucleoside triphosphates required for DNA synthesis. |
| gemcitabine pharma | Elimination is mainly by metabolism.Gemcitabine is infused IV. It is deaminated to di fluorodeoxyuridine, which is not cytotoxic, and is excreted in urine. |
| gemcitabine use | Gemcitabine was initially approved for pancreatic cancer and now is used widely in the treatment of non-small cell lung cancer, bladder cancer, and non-Hodgkin’s lymphoma. Gemcitabine is an analog of the nucleoside deoxycytidine. It is used for the first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. It also is effective against non–small cell lung cancer and several other tumors. |
| gemcitabine toxicity | Primarily myelosuppression occurs, mainly as neutropenia. Pulmonary toxicity has been observed Antimetabolites are structurally related to normal compounds that exist within the cell. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors, either by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are in S-phase (and are, therefore, cell-cycle specific).Myelosuppression is the dose-limiting toxicity of gemcitabine. Other toxicities include nausea, vomiting, alopecia, rash, and a flu-like syndrome. Transient elevations of serum transaminases, proteinuria, and hematuria are common |
| gemcitabine resistance | Resistance to the drug is probably due to its inability to be converted to a nucleotide, caused by an alteration in deoxycytidine kinase. In addition, the tumor cell can produce increased levels of endogenous deoxycytidine that compete for the kinase, thus overcoming the inhibition. |
| 6-Thioguanine (6-TG) mechanism | , a purine analog, is primarily used in the treatment of acute nonlymphocytic leukemia in combination with daunorubicin and cytarabine. Like 6-MP, 6-TG is converted intracellularly to TGMP (also called 6-thioguanylic acid) by the enzyme HGPRT. TGMP is further converted to the di- and triphosphates, thioguanosine diphosphate and thioguanosine triphosphate, which then inhibit the biosynthesis of purines and also the phosphorylation of GMP to guanosine diphosphate. The nucleotide form of 6-TG is incorporated into DNA that leads to cell-cycle arrest. |
| pharma 6-thioguanine | Similar to 6-MP, the absorption of oral 6-TG is also incomplete and erratic. The peak concentration in the plasma is reached in 2 to 4 hours after ingestion. When 6-TG is administered, it is converted to the S-methylation product, 2-amino-6-methylthiopurine by thiopurine methyltransferase (TPMT), which appears in the urine. Patients with low or intermediate TPMT activity accumulate higher concentrations of thioguanine cytotoxic metabolites compared to patients with normal TPMT activity. This results in unexpectedly high myelosuppression and has also been associated with the occurrence of secondary malignancies. Approximately 3 percent of whites and blacks express either a homozygous deletion or mutation of the TPMT gene. Because an estimated 10 percent of patients may be at increased risk for toxicity because of a heterozygous deletion or mutation of TPMT, TPMT genotyping is recommended before therapy. To a lesser extent, 6-thioxanthine and 6-thiouric acid are also formed by the action of guanase. Because the deamination product 6-thioanthine is an inactive metabolite, 6-TG may be administered along with allopurinol without any dose reduction |
| 6-thioguanine adverse effects | Bone marrow depression is the dose-related adverse effect. 6-TG is not recommended for maintenance therapy or continuous long-term treatments due to the risk of liver toxicity. |
| fludarabine moa | Fludarabine is the 5’-phosphate of 2-fl uoroadenine arabinoside, a purine nucleotide analog. It is useful in the treatment of chronic lymphocytic leukemia and may replace chlorambucil, the current drug of choice. Fludarabine is also eff ective against hairy cell leukemia and indolent non-Hodgkin lymphoma. Fludarabine is a prodrug, the phosphate being removed in the plasma to form 2-F-araA, which is taken up into cells and again phosphorylated (initially by deoxycytidine kinase). Although the exact cytotoxic mechanism is uncertain, the triphosphate is incorporated into both DNA and RNA. This decreases their synthesis in the S phase and affects their function. Resistance is associated with reduced uptake into cells, lack of deoxycytidine kinase, and decreased affinity for DNA polymerase as well as other mechanisms. Fludarabine is administered IV rather than orally, because intestinal bacteria split off the sugar to yield the very toxic metabolite, fluoroadenine. Urinary excretion accounts for partial elimination. In addition to nausea, vomiting, and diarrhea, myelosuppression is the dose-limiting toxicity. Fever, edema, and severe neurologic toxicity also occur. At high doses, progressive encephalopathy, blindness, and death have been reported. |
| cladribine | Another purine analog, 2-chlorodeoxyadenosine, or cladribine, undergoes reactions similar to those of fl udarabine, and it must be converted to a nucleotide to be cytotoxic. It becomes incorporated at the 3’-terminus of DNA and, thus, hinders elongation. It also affects DNA repair and is a potent inhibitor of ribonucleotide reductase.Resistance may be due to mechanisms analogous to those that affect fludarabine, although cross-resistance is not a problem. Cladribine is effective against hairy cell leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. It also has some activity against multiple sclerosis. The drug is given as a single, continuous infusion. Cladribine distributes throughout the body, including into the CSF. Severe bone marrow suppression is a common adverse effect, as is fever. Peripheral neuropathy has also been reported. The drug is teratogenic. |
| Capecitabine use | Capecitabine is a novel, oral fluoropyrimidine carbamate. It is approved for the treatment of metastatic breast cancer that is resistant to first-line drugs (for example, paclitaxel and anthracyclines) and is currently also used for treatment of colorectal cancer. |
| Capecitabine moa | After being absorbed, capecitabine, which is itself nontoxic, undergoes a series of enzymatic reactions, the last of which is hydrolysis to 5-FU. This step is catalyzed by thymidine phosphorylase, an enzyme that is concentrated primarily in tumors. Thus, the cytotoxic activity of capecitabine is the same as that of 5-FU and is tumor specific. The most important enzyme inhibited by 5-FU (and, thus, capecitabine) is thymidylate synthase. |
| Capecitabine pharma | Capecitabine has the advantage of being well absorbed following oral administration. It is extensively metabolized to 5-FU and is eventually biotransformed into fluoro-β-alanine and CO2. Metabolites are primarily eliminated in urine or, in the case of CO2, exhaled. |
| Capecitabine adverse effects | These are similar to those with 5-FU, with the toxicity occurring primarily in the GI tract. Capecitabine should be used cautiously in patients with hepatic or renal impairment. The drug is contraindicated in individuals who are pregnant or lactating. Patients taking coumarin anticoagulants or phenytoin should be monitored for coagulation parameters and drug levels, respectively. |
| floxuridine | Floxuridine is an analog (floxuridine is 2’-deoxy-5-fluorouridine ) of 5-FU. When given by rapid intraarterial injection, floxuridine is rapidly catabolized in the liver to 5-FU and produces antimetabolite effects. The primary effect is to interfere with the synthesis of DNA and, to a lesser extent, inhibit the formation of RNA. The drug is excreted intact and as fluorouracil, urea, and α-fluoro-β-alanine in the urine. Floxuridine is effective in the palliative management of GI adenocarcinoma that has metastasized to the liver. The common adverse effects are nausea, vomiting, diarrhea, enteritis, stomatitis, and localized erythema. |
| monoclonal antibodies | Monoclonal antibodies have become an active area of drug development for anticancer therapy and other non neoplastic diseases, because they are directed at specific targets and often have fewer adverse effects. They are created from B lymphocytes (from immunized mice or hamsters) fused with “immortal” B-lymphocyte tumor cells. The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type. Recombinant technology has led to the creation of “humanized” antibodies that overcome the immunologic problems previously observed following administration of mouse (murine) antibodies. |
| other monoclonal | Others include gemtuzumab ozogamicin,which is a monoclonal antibody conjugated with a plant toxin that binds to CD33 (a cell-surface receptor that is present on the leukemia cells of 80 percent of patients with acute myelocytic leukemia); alemtuzumab, which is effective in treatment of B-cell chronic lymphocytic leukemia that no longer responds to other agents; and I131-tositumomab, which is used in relapsed non-Hodgkin lymphoma. |
| trastuzumab use | Several drugs inhibit an epidermal growth factor receptor (EGFR) that is distinct from the HER-2/neu receptor for the epidermal growth factor that is targeted by trastuzumab. The EGFR regulates signaling pathways involved in cellular proliferation, invasion and metastasis, and angiogenesis. It is also implicated in inhibiting the cytotoxic activity of some anticancer drugs and radiation therapy. The drug, usually administered with paclitaxel, can cause regression of breast cancer and metastases in a small percentage of these individuals. [Note: At least 50 tyrosine kinases mediate cell growth or division by phosphorylating signaling proteins. They have been implicated in the development of many neoplasms by an unknown mechanism.] |
| trastuzumab moa | Several mechanisms have been proposed: for example, down regulation of HER2-receptor expression, an induction of antibody-dependent cytotoxicity, or a decrease in angiogenesis due to an effect on vascular endothelial growth factor. Efforts are being directed toward identifying those patients with tumors that are sensitive to the drug.In patients with metastatic breast cancer, overexpression of transmembrane human epidermal growth factor–receptor protein 2 (HER2) is seen in 25 to 30 percent of patients. Trastuzumab a recombinant DNA–produced, humanized monoclonal antibody, specifically targets the extracellular domain of the HER2 growth receptor that has intrinsic tyrosine kinase activity. Trastuzumab binds to HER2 sites in breast cancer tissue and inhibits the proliferation of cells that overexpress the HER2 protein, thereby decreasing the number of cells in the S phase. |
| trastuzumab iv | Trastuzumab is administered IV. Trastuzumab does not penetrate the blood-brain barrier. |
| trastuzumab adverse effects | The most serious toxicity associated with the use of trastuzumab is congestive heart failure. The toxicity is worsened if given in combination with anthracycline. Other adverse effects include infusion-related fever and chills, headache, dizziness, nausea, vomiting, abdominal pain, and back pain, but these effects are well tolerated. Cautious use of the drug is recommended in patients who are hypersensitive to the Chinese hamster ovary cell components of the proteins or to benzyl alcohol (in which case sterile water can be used in place of the bacteriostatic solution provided for preparation of the injection). |
| rituximab use | Rituximab is a monoclonal antibody that binds to a surface protein in non Hodgkin’s lymphoma cells and induces complement-mediated lysis, direct cytotoxicity, and induction of apoptosis. It is currently used with conventional anticancer drugs (eg, cyclophosphamide plus vincristine plus prednisone) in low-grade lymphomas. Rituximab is associated with hypersensitivity reactions and myelosuppression Rituximab was the first monoclonal antibody to be approved for the treatment of cancer. It is a genetically engineered, chimeric monoclonal antibody directed against the CD20 antigen that is found on the surfaces of normal and malignant B lymphocytes. CD20 plays a role in the activation process for cell-cycle initiation and differentiation. The CD20 antigen is expressed on nearly all B-cell nonHodgkin lymphomas but not in other bone marrow cells. Rituximab has proven to be effective in the treatment of posttransplant lymphoma and in chronic lymphocytic leukemia. |
| rituximab moa | The Fab domain of rituximab binds to the CD20 antigen on the B lymphocytes, and its Fc domain recruits immune effector functions, inducing complement and antibodydependent, cell-mediated cytotoxicity of the B cells. The antibody is commonly used with other combinations of anticancer agents, such as cyclophosphamide, doxorubicin, vincristine (Oncovin ), and prednisone (CHOP). |
| rituximab pharma | Rituximab is infused IV and causes a rapid depletion of B cells (both normal and malignant). The fate of the antibody has not been described. |
| rituximab adverse effects | Severe adverse reactions have been fatal. It is important to infuse rituximab slowly. Hypotension, bronchospasm, and angioedema may occur. Chills and fever commonly accompany the first infusion, especially in patients with high circulating levels of neoplastic cells, because of rapid activation of complement, which results in the release of tumor necrosis factor α and interleukins. Pretreatment with diphenhydramine, acetaminophen, and bronchodilators can ameliorate these problems. Cardiac arrhythmias can also occur. Tumor lysis syndrome has been reported within 24 hours of the first dose of rituximab. This syndrome consists of acute renal failure that may require dialysis, hyperkalemia, hypocalcemia, hyperuricemia, and hyperphosphatasemia (an abnormally high content of alkaline phosphatase in the blood). Leukopenia, thrombocytopenia, and neutropenia have been reported in less than 10 percent of patients. |
| Bevacizumab | The monoclonal antibody bevacizumab is the first in a new class of anticancer drugs called antiangiogenesis agents. Bevacizumab is approved for use as a first-line drug against metastatic colorectal cancer and is given with 5-FU-based chemotherapy. Bevacizumab is infused IV. It attaches to and stops vascular endothelial growth factor from stimulating the formation of new blood vessels. Without new blood vessels, tumors do not receive the oxygen and essential nutrients necessary for growth and proliferation. The most common adverse effects of this treatment are hypertension, stomatitis, and diarrhea. Less common are bleeding in the intestines, protein in the urine, and heart failure. Among the rare serious side effects are bowel perforation, opening of healed wounds, and stroke. Bevacizumab is a monoclonal antibody that binds to vascular endothelial growth factor (VEGF) and prevents it from interacting with VEGF receptors. VEGF plays a critical role in the angiogenesis required for tumor metastasis. Bevacizumab has activity in colorectal, breast, non-small cell lung, and renal cancer. Adverse effects include hypertension, infusion reactions, arterial thrombosis, impaired wound healing, gastrointestinal perforation, and proteinuria. Ziv-aflibercept also interferes with VEGF function. It is a recombinant fusion protein of the VEGF binding portions from the extracellular domains of human VEGF receptors 1 and 2, fused to the Fc portion of human IgG1. |
| Cetuximab | Cetuximab is another chimeric monoclonal antibody that has recently been approved to treat colorectal cancer. It is believed to exert its antineoplastic effect by targeting the epidermal growth factor receptor on the surface of cancer cells and interfering with their growth.It is used in combination with irinotecan and oxaliplatin for metastatic colon cancer and is used in combination with radiation for head and neck cancer. Like other antibodies, it is administered IV. Cetuximab has caused difficulty breathing and low blood pressure during the first treatment, and interstitial lung disease has been reported. Its primary toxicity is skin rash and a hypersensitivity infusion reaction. |
| pantimumab | Panitumumab is a fully human monoclonal antibody directed against the EGFR; it is approved for refractory metastatic colorectal cancer. |
| Gefitinib and erlotinib | Gefitinib and erlotinib are small molecule inhibitors of the EGFR’s tyrosine kinase domain. Both are used as second-line agents for non-small cell lung cancer, and erlotinib is also used in combination therapy of advanced pancreatic cancer. |
| Sorafenib, sunitinib, and pazopanib | Sorafenib, sunitinib, and pazopanib are small molecules that inhibit multiple receptor tyrosine kinases (RTKs), including those associated with the VEGF receptor family. They are metabolized by CYP3A4, and elimination is primarily hepatic. Hypertension, bleeding complications, and fatigue are the most common adverse effects. |
| alkylating agents | The alkylating agents include nitrogen mustards (chlorambucil, cyclophosphamide, mechlorethamine), nitrosoureas (carmustine, lomustine), and alkyl sulfonates (busulfan). Other drugs that act in part as alkylating agents include cisplatin, dacarbazine, and procarbazine. |
| alkylating agent action | The alkylating agents are CCNS drugs. They form reactive molecular species that alkylate nucleophilic groups on DNA bases, particularly the N-7 position of guanine. This leads to crosslinking of bases, abnormal base-pairing, and DNA strand breakage. Tumor cell resistance to the drugs occurs through increased DNA repair, decreased drug permeability, and the production of trapping agents such as thiols. Alkylating agents exert their cytotoxic effects by covalently binding to nucleophilic groups on various cell constituents. Alkylation of DNA is probably the crucial cytotoxic reaction that is lethal to the tumor cells. Alkylating agents do not discriminate between cycling and resting cells, but they are most toxic for rapidly dividing cells. They are used in combination with other agents to treat a wide variety of lymphatic and solid cancers. In addition to being cytotoxic, all are mutagenic and carcinogenic and can lead to secondary malignancies such as acute leukemia. |
| cyclophosphamide use | These drugs are very closely related mustard agents that share most of the same primary mechanisms and toxicities. They are unique in that they can be taken orally and are cytotoxic only after generation of their alkylating species, which are produced through hydroxylation by cytochrome P450 (CYP450). These agents have a broad clinical spectrum, being used either singly or as part of a regimen in the treatment of a wide variety of neoplastic diseases, such as Burkitt lymphoma and breast cancer. Nonneoplastic disease entities, such as nephrotic syndrome and intractable rheumatoid arthritis, are also effectively treated with low doses of cyclophosphamide, include leukemia, non-Hodgkin’s lymphoma, breast and ovarian cancers, and neuroblastoma. |
| cyclophosphamide moa | Hepatic cytochrome P450-mediated biotransformation of cyclophosphamide is needed for antitumor activity. One of the breakdown products is acrolein.Unlike most of the alkylating agents, cyclophosphamide and ifosfamide can be administered by the oral route After oral administration, minimal amounts of the parent drug are excreted into the feces (after biliary transport) or into the urine by glomerular filtration. |
| cyclophophamide toxicity | Gastrointestinal distress, myelosuppression, and alopecia are expected adverse effects of cyclophosphamide. Hemorrhagic cystitis resulting from the formation of acrolein may be decreased by vigorous hydration and by use of mercaptoethanesulfonate (mesna). Cyclophosphamide may also cause cardiac dysfunction, pulmonary toxicity, and a syndrome of inappropriate antidiuretic hormone (ADH) secretion The most prominent toxicities of both drugs (after alopecia, nausea, vomiting, and diarrhea) are bone marrow depression, especially leukocytosis, and hemorrhagic cystitis, which can lead to fibrosis of the bladder. The latter toxicity has been attributed to acrolein in the urine in the case of cyclophosphamide and to toxic metabolites of ifosfamide. [Note: Adequate hydration as well as IV injection of MESNA (sodium 2-mercaptoethane sulfonate), which neutralizes the toxic metabolites, minimizes this problem.] Other toxicities include effects on the germ cells, resulting in amenorrhea, testicular atrophy, aspermia, and sterility. Veno-occlusive disease of the liver is seen in about 25 percent of the patients. A fairly high incidence of neurotoxicity has been reported in patients on high-dose ifosfamide, probably due to the metabolite, chloroacetaldehyde. Secondary malignancies may appear years after therapy. |
| moa: Cyclophosphamide | Cyclophosphamide is the most commonly used alkylating agent. Both cyclophosphamide and ifosfamide are first biotransformed to hydroxylated intermediates primarily in the liver by the CYP450 system The hydroxylated intermediates then undergo breakdown to form the active compounds, phosphoramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step. |
| resistance Cyclophosphamide | Resistance results from increased DNA repair, decreased drug permeability, and reaction of the drug with thiols (for example, glutathione). Cross-resistance does not always occur. |
| Mechlorethamine use | Mechlorethamine was developed as a vesicant (nitrogen mustard) during World War I. Its ability to cause lymphocytopenia led to its use in lymphatic cancers. Because it can covalently attach to two separate nucleotides, such as guanine on the DNA molecules, it is called a “bifunctional agent.” Mechlorethamine was used primarily in the treatment of Hodgkin disease and may find use in the treatment of some solid tumors. |
| pharma: Mechlorethamine | is very unstable, and solutions must be made up just prior to administration. Mechlorethamine is also a powerful vesicant (blistering agent) and is only administered IV. Because of its reactivity, scarcely any drug is excreted. |
| mechlorethamine mechanism | Mechlorethamine spontaneously converts in the body to a reactive cytotoxic product.Mechlorethamine is transported into the cell, where the drug forms a reactive intermediate that alkylates the N7 nitrogen of a guanine residue in one or both strands of a DNA molecule This alkylation leads to cross-linkages between guanine residues in the DNA chains and/or depurination, thus facilitating DNA strand breakage. Alkylation can also cause miscoding mutations. Although alkylation can occur in both cycling and resting cells (and, therefore, is cell-cycle nonspecific), proliferating cells are more sensitive to the drug, especially those in the G1 and S phases. |
| mechlorethamine resistance | Resistance has been ascribed to decreased permeability of the drug, increased conjugation with thiols such as glutathione, and, possibly, increased DNA repair. |
| mechlorethamine toxicity | Gastrointestinal distress, myelosuppression, alopecia, and sterility are common. Mechlorethamine has marked vesicant (blister-forming) actions.The include severe nausea and vomiting (centrally mediated). [Note: These eff ects can be diminished by pretreatment with ondansetron, granisetron, or palonosetron with dexamethasone.] Severe bone marrow depression limits extensive use. Latent viral infections (for example, herpes zoster) may appear because of immunosuppression. Extravasation is a serious problem. If it occurs, the area should be infiltrated with isotonic sodium thiosulfi te to inactivate the drug. |
| Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin) pharma | The platinum agents are used intravenously; the drugs distribute to most tissues and are cleared in unchanged form by the kidney. |
| Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin)clinical use | 2. Clinical use—Cisplatin is commonly used as a component of regimens for testicular carcinoma and for cancers of the bladder, lung, and ovary. Carboplatin has similar uses. Oxaliplatin is used in advanced colon cancer. |
| Platinum Analogs (Cisplatin, Carboplatin, Oxaliplatin) toxicity | Cisplatin causes gastrointestinal distress and mild hematotoxicity and is neurotoxic (peripheral neuritis and acoustic nerve damage) and nephrotoxic. Renal damage may be reduced by the use of mannitol with forced hydration. Carboplatin is less nephrotoxic than cisplatin and is less likely to cause tinnitus and hearing loss, but it has greater myelosuppressant actions. Oxaliplatin causes dose-limiting neurotoxicity. |
| Procarbazine mechanisms | Procarbazine is a reactive agent that forms hydrogen peroxide, which generates free radicals that cause DNA strand scission. |
| Procarbazine pharma | Procarbazine is orally active and penetrates into most tissues, including the cerebrospinal fluid. It is eliminated via hepatic metabolism. |
| Procarbazine clinical use | The primary use of the drug is as a component of regimens for Hodgkin’s and non-Hodgkin’s lymphoma, and brain tumors. |
| Procarbazine toxicity | Procarbazine is a myelosuppressant and causes gastrointestinal irritation, CNS dysfunction, peripheral neuropathy, and skin reactions. Procarbazine inhibits many enzymes, including monoamine oxidase and those involved in hepatic drug metabolism. Disulfiram-like reactions have occurred with ethanol. The drug is leukemogenic. |
| Nitrosoureas use | Carmustine and lomustine are closely related nitrosoureas. Because of their ability to penetrate the CNS, the nitrosoureas are primarily employed in the treatment of brain tumors. They find limited use in the treatment of other cancers. [Note: Streptozocin is another nitrosourea that is specifically toxic to the β cells of the islets of Langerhans, hence its use in the treatment of insulinomas.] |
| Nitrosoureas moa | The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication and, eventually, RNA and protein synthesis. Although they alkylate DNA in resting cells, cytotoxicity is expressed primarily on cells that are actively dividing. Therefore, nondividing cells can escape death if DNA repair occurs. Nitrosoureas also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins in the targeted cells. |
| Nitrosoureas resistance | Although the true nature of resistance to nitrosoureas is unknown, it probably results from DNA repair and reaction of the drugs with thiols. |
| Nitrosoureas pharma | In spite of the similarities in their structures, carmustine is administered IV, whereas lomustine is given orally. Because of their lipophilicity , they distribute widely in the body to many tissues, but their most striking property is their ability to readily penetrate the CNS. The drugs undergo extensive metabolism. Lomustine is metabolized to active products. The kidney is the major excretory route for the nitrosoureas |
| Nitrosoureas adverse effects | These include delayed hematopoietic depression, which may be due to metabolic products. An aplastic marrow may develop on prolonged use. Renal toxicity and pulmonary fibrosis related to duration of therapy is also encountered. [Note: Streptozotocin is also diabetogenic.] |
| Dacarbazine use | Dacarbazine is used in regimens for Hodgkin’s lymphoma. It causes alopecia, skin rash, gastrointestinal distress, myelosuppression, phototoxicity, and a flu-like syndrome. found use in the treatment of melanoma, is an alkylating agent that must undergo biotransformation to an active metabolite, methyltriazenoimidazole carboxamide (MTIC). This metabolite is responsible for the drug’s activity as an alkylating agent by forming methylcarbonium ions that can attack the nucleophilic groups in the DNA molecule. Thus, similar to other alkylating agents, the cytotoxic action of dacarbazine has been attributed to the ability of its metabolite to methylate DNA on the O6 position of guanine. Dacarbazine is administered IV. |
| dacarzabine adverse effect | Its major adverse effects are nausea and vomiting. Myelosuppression (thrombocytopenia and neutropenia) occur later in the treatment cycle. Hepatotoxicity with hepatic vascular occlusion may also occur in long-term treatments. |
| Temozolomide use | The treatment of tumors in the brain is particularly difficult. Recently, temozolomide, a triazene agent, has been approved for use against treatment-resistant gliomas and anaplastic astrocytomas. |
| temozolomide pharma | Temozolomide is related to dacarbazine, because both must undergo biotransformation to an active metabolite, MTIC, which probably is responsible for the methylation of DNA on the 6 positionof guanine. Unlike dacarbazine, temozolomide does not require the CYP450 system for metabolic transformation, and it undergoes chemical transformation under normal physiological pH. Temozolomide also has the property of inhibiting the repair enzyme, O6-guanineDNA-alkyltransferase. A property that distinguishes temozolomide from dacarbazine is the former’s ability to cross the blood-brain barrier. Temozolomide is taken orally and has excellent oral bioavailability.he parent drug and metabolites are excreted in urine Temozolomide is taken for 5 consecutive days and repeated every 28 days. |
| temozolomide adverse effect | Similar to dacarbazine, its major initial toxicities are nausea and vomiting. Myelosuppression (thrombocytopenia and neutropenia) occur later in the treatment cycle. |
| melphalan | Melphalan , a phenylalanine derivative of nitrogen mustard, is used in the treatment of multiple myeloma. This is a bifunctional alkylating agent that can be given orally. Although melphalan can be given orally, the plasma concentration differs from patient to patient due to variation in intestinal absorption and metabolism. The dose of melphalan is carefully adjusted by monitoring the platelet and white blood cell counts. |
| chlorambucil | Chlorambucil is another bifunctional alkylating agent that is used in the treatment of chronic lymphocytic leukemia. Both melphalan and chlorambucil have moderate hematologic toxicities and upset the GI tract. |
| busulfan | Busulfan is another oral agent that is effective against chronic granulocytic leukemia. Busulfan is also a bifunctional alkylating agent that can cause myelosuppression. In aged patients, busulfan can cause pulmonary fi brosis. Like other alkylating agents, all of these agents are leukemo genic.Busulfan is sometimes used in chronic myelogenous leukemia. It causes adrenal insufficiency, pulmonary fibrosis, and skin pigmentation. |
| The Log-Kill Hypothesis | The log-kill hypothesis proposes that the magnitude of tumor cell kill by anticancer drugs is a logarithmic function. For example, a 3-log-kill dose of an effective drug reduces a cancer cell population of 1012 cells to 109 (a total kill of 999 × 109 cells); the same dose would reduce a starting population of 106 cells to 103 cells (a kill of 999 × 103 cells). In both cases, the dose reduces the numbers of cells by 3 orders of magnitude, or “3 logs.” A key principle that stems from this finding and that is applicable to hematologic malignancies is an inverse relationship between tumor cell number and curability Mathematical modeling data suggest that most human solid tumors do not grow in such an exponential manner and rather that the growth fraction of the tumor decreases with time owing to blood supply limitations and other factors. In drug-sensitive solid tumors, the response to chemotherapy depends on where the tumor is in its growth curve. Therefore, almost all antitumor agents have a steep dose-response curve for both toxic and therapeutic effects. |
| Resistance to Anticancer Drugs by increased dna repair | An increased rate of DNA repair in tumor cells can be responsible for resistance and is particularly important for alkylating agents and cisplatin. |
| Resistance to Anticancer Drugs by formation of trapping agents | Some tumor cells increase their production of thiol trapping agents (eg, glutathione), which interact with anticancer drugs that form reactive electrophilic specie This mechanism of resistance is seen with the alkylating agent bleomycin, cisplatin, and the anthracyclines. |
| Resistance to Anticancer Drugs by changes in target enzymes | Changes in the drug sensitivity of a target enzyme, dihydrofolate reductase, and increased synthesis of the enzyme are mechanisms of resistance of tumor cells to methotrexate |
| Resistance to Anticancer Drugs by decreased activation of profrug | Resistance to the purine antimetabolites (mercaptopurine, thioguanine) and the pyrimidine antimetabolites (cytarabine, fluorouracil) can result from a decrease in the activity of the tumor cell enzymes needed to convert these prodrugs to their cytotoxic metabolites. |
| Resistance to Anticancer Drugs by inactivated anticancer drugs | Increased activity of enzymes capable of inactivating anticancer drugs is a mechanism of tumor cell resistance to most of the purine and pyrimidine antimetabolites. |
| Resistance to Anticancer Drugs by decreasing drug accumulation | This form of multidrug resistance involves the increased expression of a normal gene (MDR1) for a cell surface glycoprotein (P-glycoprotein). This transport molecule is involved in the accelerated efflux of many anticancer drugs in resistant cells. |
| Primary induction chemotherapy— | Drug therapy is administered as the primary treatment for many hematologic cancers and for advanced solid tumors for which no alternative treatment exists. Although primary induction can be curative in a small number of patients who present with advanced metastatic disease (eg, lymphoma, acute myelogenous leukemia, germ cell cancer, choriocarcinoma, and several childhood cancers), in many cases the goals of therapy are palliation of cancer symptoms, improved quality of life, and increased time to tumor progression. |
| Neoadjuvant chemotherapy— | The use of chemotherapy in patients who present with localized cancer for which alternative local therapy, such as surgery, exist is known as neoadjuvant chemotherapy. The goal is to render the local therapy more effective. |
| Adjuvant chemotherapy— | In the treatment of many solid tumors, chemotherapy serves as an important adjuvant to local treatment procedures such as surgery or radiation. The goal is to reduce the risk of local and systemic recurrence and to improve disease-free and overall survival. |
| principles important for selecting appropriate drugs to use in combination chemotherapy | (1) Each drug should be active when used alone against the particular cancer.
2) The drugs should have different mechanisms of action.
(3) Cross-resistance between drugs should be minimal.
(4) The drugs should have different toxic effects |
| rescue therapy | high doses of methotrexate may be given for 36–48 h and terminated before severe toxicity occurs to cells of the gastrointestinal tract and bone marrow. Leucovorin, a form of tetrahydrofolate that is accumulated more readily by normal than by neoplastic cells, is then administered. This results in rescue of the normal cells because leucovorin bypasses the dihydrofolate reductase step in folic acid synthesis. |
| mesna traps | Mercaptoethanesulfonate (mesna) “traps” acrolein released from cyclophosphamide and thus reduces the incidence of hemorrhagic cystitis. |
| dexrazoxane | Dexrazoxane inhibits free radical formation and affords protection against the cardiac toxicity of anthracyclines (eg, doxorubicin). |
| Indications for treatment: | Chemotherapy is indicated when neoplasms are disseminated and are not amenable to surgery. Chemotherapy is also used as a supplemental treatment to attack micrometastases following surgery and radiation treatment, in which case it is called adjuvant chemotherapy. Chemotherapy given prior to the surgical procedure in an attempt to shrink the cancer is referred to as neoadjuvant chemotherapy, and chemotherapy given in lower doses to assist in prolonging a remission is known as maintenance chemotherapy. |
| Tumor susceptibility and the growth cycle | The fraction of tumor cells that are in the replicative cycle (“growth fraction”) influences their susceptibility to most cancer chemotherapeutic agents. Rapidly dividing cells are generally more sensitive to anticancer drugs, whereas slowly proliferating cells are less sensitive to chemotherapy. In general, nonproliferating cells (those in the G0 phase sually survive the toxic effects of many of these agents. |
| cycle specific and non specific agents | Chemotherapeutic agents that are effective only against replicating cells (that is, those cells that are cycling) are said to be cell-cycle specific whereas other agents are said to be cell-cycle nonspecific. The nonspecific drugs, although having generally more toxicity in cycling cells, are also useful against tumors that have a low percentage of replicating cells. |
| Pharmacologic sanctuaries: | Leukemic or other tumor cells find sanctuary in tissues such as the central nervous system (CNS), where transport constraints prevent certain chemotherapeutic agents from entering. Therefore, a patient may require irradiation of the craniospinal axis or intrathecal administration of drugs to eliminate the leukemic cells at that site. Similarly, drugs may be unable to penetrate certain areas of solid tumors. |
| Treatment protocols: | Combination-drug chemotherapy is more successful than single-drug treatment in most of the cancers for which chemotherapy is effective. Cytotoxic agents with qualitatively different toxicities, and with diff erent molecular sites and mechanisms of action, are usually combined at full doses.this results in higher response rates, due to additive and/or potentiated cytotoxic eff ects, and nonoverlapping host toxicities. In contrast, agents with similar dose-limiting toxicities,such as myelosuppression, nephrotoxicity, or cardiotoxicity, can be combined safely only by reducing the doses of each. |
| Advantages of drug combinations: | The advantages of such drug combinations are that they 1) provide maximal cell killing within the range of tolerated toxicity, 2) are eff ective against a broader range of cell lines in the heterogeneous tumor population, and 3) may delay or prevent the development of resistant cell lines. |
| treatment formulation | Many cancer treatment protocols have been developed, and each one is applicable to a particular neoplastic state. They are usually identified by an acronym. . Therapy is scheduled intermittently (approximately 21 days apart) to allow recovery of the patient’s immune system, which is also affected by the chemotherapeutic agent, thus reducing the risk of serious infection. |
| drug resistance minimized | The development of drug resistance is minimized by short-term, intensive, intermittent therapy with combinations of drugs. Drug combinations are also effective against a broader range of resistant cells in the tumor population. A variety of mechanisms are responsible for drug resistance, each of which is considered separately in the discussion of a particular drug. |
| multidrug resistance | Stepwise selection of an amplified gene that codes for a transmembrane protein (P-glycoprotein for “permeability” glycoprotein is responsible for multidrug resistance. This resistance is due to adenosine triphosphate–dependent pumping of drugs out of the cell in the presence of P-glycoprotein. Crossresistance following the use of structurally unrelated agents also occurs. For example, cells that are resistant to the cytotoxic effects of the vinca alkaloids are also resistant to dactinomycin and to the anthracycline antibiotics as well as to colchicine, and vice versa. These drugs are all naturally occurring substances, each of which has a hydrophobic aromatic ring and a positive charge at neutral pH. [Note: P-glycoprotein is normally expressed at low levels in most cell types, but higher levels are found in the kidney, liver, pancreas, small intestine, colon, and adrenal gland. It has been suggested that the presence of P-glycoprotein may account for the intrinsic resistance to chemotherapy observed with adenocarcinomas.] Certain drugs at high concentrations (for example, verapamil) can inhibit the pump and, thus, interfere with the efflux of the anticancer agent. However, these drugs are undesirable because of adverse pharmacologic actions of their own. Pharmacologically inert pump blockers are being sought. |
| Common adverse effects: | Most chemotherapeutic agents have a narrow therapeutic index. Severe vomiting, stomatitis, bone marrow suppression, and alopecia occur to a lesser or greater extent during therapy with all antineoplastic agents. Vomiting is often controlled by administration of antiemetic drugs. Some toxicities, such as myelosuppression that predisposes to infection, are common to many chemotherapeutic agents whereas other adverse reactions are confined to specific agents, such as, bladder toxicity with cyclophosphamide, cardiotoxicity with doxorubicin, and pulmonary fibrosis with bleomycin. The duration of the side effects varies widely. For example, alopecia is transient, but the cardiac, pulmonary, and bladder toxicities are irreversible. |
| b. Minimizing adverse effects: | Some toxic reactions may be ameliorated by interventions, such as the use of cytoprotectant drugs, perfusing the tumor locally (for example, a sarcoma of the arm), removing some of the patient’s marrow prior to intensive treatment and then reimplanting it, or promoting intensive diuresis to prevent bladder toxicities. The megaloblastic anemia that occurs with methotrexate can be effectively counteracted by administering folinic acid (leucovorin, 5-formyltetrahydrofolic acid; With the availability of human granulocyte colony– stimulating factor (fi lgrastim), the neutropenia associated with treatment of cancer by many drugs can be partially reversed. |
| Treatment-induced tumors: | Because most antineoplastic agents are mutagens, neoplasms (for example, acute nonlymphocytic leukemia) may arise 10 or more years after the original cancer was cured. [Note: Treatment-induced neoplasms are especially a problem after therapy with alkylating agents.] |
