CANCER
All cancers have a few clinical and pathological characteristics in common, but those arising in different organs often have very different causes. The disruption of proteins with pivotal roles in cell growth, death, and the regulation of gene expression is the underlying cause of cancer. The most common causes of these disturbances are somatic mutations that accumulate in cellular DNA over time, induced by chemicals in the environment (carcinogens), radiation, or simply the background rate of error in DNA replication. On occasion, carcinogenic mutations are inherited ('germline' mutations).
The genes responsible for cancer show that they can be broadly divided into two operational classes: tumour suppressor genes and oncogenes. Oncogenes are associated with mutant proteins demonstrating a gain in function, which over stimulate cell division or support the survival of genetically aberrant cells. In contrast, tumour suppressor genes are characterized by mutations that cause a loss of function. Typically, tumour suppressor genes encode proteins that suppress cellular proliferation, activate cell death pathways, or protect the integrity of the genome in the presence of DNA damage. In general, inactivation of both alleles of a tumour suppressor gene is required before aberrant cellular behavior is evident.
Cancer is a common disease. Management of suspected cancer would be improved greatly if the following simple rules were adhered to:
1. Cancer should be suspected with any unexplained illness, especially in the elderly.
2. Imaging with isotopic and computed tomography (CT) and magnetic resonance imaging (MRI), will often accelerate diagnosis.
3. Patients with many tumours should start a planned programme of treatment within days and not weeks of diagnosis.
Common symptoms and signs of cancer: Pain, Weight loss, Fever, Anaemia, Hypercalcaemia, Paraneoplastic syndromes.
Histopathological diagnosis: The investigation of a cancer is to verify that the diagnosis is correct.
Surgical cancer: The cancer can be prevented or treated by some surgical procedures.
Prevention: Avoiding carcinogens or altering their metabolism, exposure to chemical carcinogens, Pursuing a life style or diet such as alcohol, smoking.
Treatment: Anti neoplastic agents are the most effective drugs in treating many types of malignancies because they destroy malignant cells and are effective against rapidly multiplying cells.
1. Alkylating agents:
A. Nitrogen mustards: chlorambucil, mechlorethamine, cyclophosphamide, estramustein, ifosfamide
B. Ethylene amines: Thiotepa
D. Sulphar mustards: Pepstatin
E. Platinum derivatives: cisplatin, carboplatin, nadeplatin, oxaleplatin
G. Alkyl sulfonates: Busulphan, treosulphan
2. Antimetabolites:
A. Folic acid antagonist: methotraxate
B. Purine antagonist: 6-thioguanine, 6- Mercaptopurine, thalidomide
C. Pyrimidine antagonist: 5-flurouracil, cytarabine, capecitabine, gemcitabine
3. Antibiotics: Actinomycin-D/dactinomycin, doxorubicin, daunorubicin, mitomycin-C
4. Plant derivatives:
A.Vinka alkaloids: Vincristin, vinblastin, vindesine.
B. Epipodophyllotoxins: Etoposide, teleposide
C.Camptothecin: Topotecan, irinotecan
D.Taxanes: Paclitaxel, docetaxel
E.enzymes: L-asperginase
F.Miscellaneous: Hydroxyl urea, carboplatin
5. Tyrosine kinase inhibitors: Imatinib mesylate
6. Epidermal growth factor inhibitors: Gefitinib,eriotinib
7. Proteosome inhibitors: Bortezomib
8. Harmonal antagonist:
A.Somatostatin inhibitors: Octreatide
B.Gonadotropin releasing harmone agonist: Gosereline, busereline, nafereline
C.Gonadotropin releasing harmone antagonist: Genirelix, cetorelix
D.Corticosteroids: Prednisolone, Dexamethasone
E.Adreno cortical suppressents: Aminoglutathimide
F.Estrogen receptor blockers: Tamoxifen, raloxifen
G.Androgen receptor antagonist: Flutamide, nilutamide, cyproterane
H.Progesterones: Hydroxyl progesterone, megesterol acetate
I. Estrogens: Diethyl stilboestrol, ethinyl estradiol
J.Androgens: Testosterone propionate
9. Monoclonal antibodies:
A. Naked monoclonal antibodies: rituximab, Transtuzumab
B. Cytotoxic conjugates: Gemtuzumab
C. Radio isotopes: I131, tostufumomab
10. Cytoprotectants:
A. Colony stimulating factors: Falgramastin, sargramastin
B.Thiophosphate cytoprotectents: Amifostein
C.Iron chelators: Derazoxane
D.Acrolein conjugator: Mesna
E.Thrombopoietic growth factors: Oprelvikin thrombopoitin
F.Others: Levamisole
Alkylating Agents:
These agents exerted their cytotoxic effects covalently by binding to a nucleophilic group on a various cell constituents. DNA Alkylation is probably the crucial cytotoxic reaction that is lethal to the tumor cells. They are used in combination with other agents to treat a wide variety of lymphatic and solid cancers.
Mechlorethamine: Mechlorethamine was developed as nitrogen mustard during World War I. Its ability to cause lymphocytopenia lead to its use in lymphatic cancers. Because it can covalently attach to two separate nucleotides, such as guanine on the DNA molecules. Mechlorethamine was used primarily in the treatment of Hodgkin's disease and may find use in the treatment of some solid tumors.
Mechanism of action: Mechlorethamine is transported into the cell, where the drug forms a reactive intermediate that alkylate the nitrogen N7of a guanine residue in one or both strands of a DNA molecule. The alkylation of nitrogen leads to the cross-linkages between the guanine residues in the DNA chains and/or depurination, thus facilitating DNA strand breakage. The alkylation can also be cause a miscoding mutations. Although alkylation can occur in both cycling and resting cells, proliferating cells are more sensitive to the drug, especially those in the G1 and S phases.
Resistance: The resistance has been described to decrease the permeability of a drug, increased conjugation with thiols such as glutathione, and possibly, increased DNA repair.
Pharmacokinetics: Mechlorethamine is very unstable, and solutions must be made up just prior to administration. Mechlorethamine is also a powerful vesicant and is only administered IV. Because of its reactivity, scarcely any drug is excreted.
Adverse effects: The adverse effects caused by mechlorethamine include severe nausea, bone marrow depression, vomiting and Latent viral infections.
Cyclophosphamide and ifosfamide: 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. 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's lymphoma and breast cancer. Non-neoplastic disease entities, such as intractable rheumatoid arthritis and nephritic syndrome, are also effectively treated with low doses of cyclophosphamide.
Mechanism of action: Cyclophosphamide is the most commonly used alkylating agent. Both ifosfamide and cyclophosphamide are the first biotransformed to hydroxylated intermediates primarily in the liver by the cytochrome P450 system. The hydroxylated intermediates then undergo breakdown to form the active compounds, acrolein and phosphoramide mustard. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step.
Resistance: Resistance results from increased DNA repair, decreased drug permeability, and reaction of the drug with thiols (glutathione). Cross-resistance does not always occur.
Pharmacokinetics: 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.
Adverse effects: Alopecia, vomiting, nausea, bone marrow depression, diarrhea, leukocytosis, hemorrhagic cystitis. Other toxicities include effects on the germ cells, resulting in testicular atrophy, amenorrhea, aspermia, and sterility.
Nitrosoureas: Lomustine and Carmustine are the closely related nitrosoureas. Because of their ability to penetrate into the CNS, the nitrosoureas are primarily employed in the treatment of brain tumors. They find limited use in the treatment of other cancers.
Mechanism of action: The nitrosoureas exert cytotoxic effects by an alkylation that inhibits replication of RNA and protein synthesis and also they alkylate DNA in resting cells, cytotoxicity is expressed primarily on cells that are actively dividing. Therefore, non dividing cells can escape death if DNA repair occurs.
Resistance: Although the true nature of resistance to nitrosoureas is unknown, it probably results from DNA repair and reaction of the drugs with thiols.
Pharmacokinetics: 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 into the CNS. The drugs undergo extensive metabolism. Lomustine is metabolized to active products. The kidney is the major excretory route for the 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.
Cisplatin: It has antitumor activity in a broad range of chronic tumors, which includes a small cell and non-small cell lung cancer, head and neck cancer, esophageal and gastric cancer, and genitourinary cancers, particularly ovarian, testicular, and bladder cancer. When used in combination regimens, cisplatin- based therapy has led to the cure of non seminomatous testicular cancer. Cisplatin and the other platinum analogs are cleared extensively by kidneys and excreted in the urine. As a result, dose modification is required in patients with renal dysfunction.
Carboplatin: It is a second-generation platinum analog whose mechanisms of cytotoxic action, mechanisms of resistance, and clinical pharmacology are identical to those described for cisplatin. As with cisplatin, carboplatin has broad-spectrum activity against a wide range of solid tumors. However, in contrast to cisplatin, it exhibits significantly less renal toxicity and gastrointestinal toxicity. Its main dose-limiting toxicity is myelosuppression. It has therefore been widely used in the transplantation regimens to treat refractory hematologic malignancies.
Dacarbazine: Dacarbazine an agent that has found use in the treatment of melanoma is an alkylating agent that must undergo biotransformation to an active metabolite, methyl triazenoimidazole 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. Dacarbazine is administered by IV. 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.
Procarbazine: Procarbazine is an orally active methyl hydrazine derivative, it is used in combination regimens for Hodgkin’s and non-Hodgkin’s lymphoma as well as brain tumors.
Mechanism of action: It inhibits DNA, RNA, and protein biosynthesis; prolongs interphase; and produces chromosome breaks. Oxidative metabolism of this drug by microsomal enzymes generates azoprocarbazine and hydrogen peroxide, which may be responsible for DNA strand scission.
Antimetabolites:
These are the structurally related to normal compounds that exist within the cell. They generally interfere with the availability of the normal pyrimidine or purine nucleotide precursors, either by inhibiting their synthesis or by competing with them in RNA or DNA synthesis. Their maximal cytotoxic effects are in S-phase.
Methotrexate: The vitamin folic acid plays a central role in a variety of metabolic reactions involving the transfer of one-carbon units1 and is essential for cell replication. Methotrexate is structurally related to folic acid and it acts as an antagonist of that vitamin by inhibiting DHF reductase2 enzyme that converts folic acid to its active, coenzyme form, tetrahydrofolic acid.
Mechanism of action: Folic acid is obtained from dietary sources or from that produced by intestinal flora. It undergoes reduction to the tetrahydrofolate form (FH4) via a reaction catalyzed by 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. Although these molecules include the nucleotides guanine, adenine, and thymidine and the amino acids such as serine and methionine and the depletion of thymidine is the most prominent effect. This leads to depression of DNA, RNA, and protein synthesis and, ultimately, leads to the cell death.
Resistance: Non proliferating cells are resistant to MTX, probably because of a relative lack of DHFR, thymidylate synthase, and/or the glutamylating enzyme. Decreased levels of the MTX polyglutamate have been reported in resistant cells and may be due to its decreased formation or increased breakdown.
Pharmacokinetics: Absorbed at low doses from the GI tract, but it can also be administered by intramuscular, intravenous (IV), and intrathecal routes. High concentrations of the drug are found in the intestinal epithelium, liver, and kidney as well as in ascites and pleural effusions. MTX is also distributed to the skin.
Adverse effects: Nausea, diarrhea, vomiting, and stomatitis, myelosuppression, alopecia, rash, erythema and urticaria. Renal damage, cirrhosis, cough, dysponea, fever, and cyanosis. Sub acute 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.
Contraindications An abortifacient, it should be avoided in pregnancy.
Therapeutic uses: Acute lymphocytic leukemia, Burkitt's lymphoma in children, and head and neck carcinomas breast cancer, choriocarcinoma,. In addition, low-dose MTX is effective as a single agent against certain diseases of inflammation, such as rheumatoid arthritis, severe psoriasis and as well as Crohn's disease. All patients receiving MTX require close monitoring for possible toxic effects.
6-Mercaptopurine: The drug 6-mercaptopurine (6-MP) is the thiol analog of hypoxanthine. 6-thioguanine and 6-MP were the first purine analogs that ar proved beneficial for treating neoplastic disease.
Mechanism of action: Nucleotide formation: 6-MP must penetrates into a target cells and be converted to the nucleotide analog, To exert its anti-leukemic effect, 6-MP-ribose phosphate (better known as 6-thioinosinic acid, or TIMP). The addition of the ribose phosphate is catalyzed by the hypoxanthine-guanine phosphoribosyl transferase and salvage pathway enzyme.
Inhibition of purine synthesis: A number of metabolic processes involved in the purine biosynthesis and interconversions are affected by the nucleotide analog, TIMP. Like guanosine monophosphate (GMP), adenosine monophosphate (AMP), and inosine monophosphate (IMP), TIMP can inhibit the 1st step of a de novo purine-ring biosynthesis. This results in a nonfunctional RNA and DNA.
Resistance: Resistance is associated with increased dephosphorylation, or increased metabolism of the drug to thiouric acid or other metabolites.
Pharmacokinetics: Absorption by the oral route is erratic and incomplete; the drug is widely distributed throughout the body, except cerebrospinal fluid. The bioavailability of 6-MP can be reduced by the first-pass metabolism in the liver. The parent drug and its metabolites are excreted by the kidney.
Adverse effects: Bone marrow depression is the principal toxicity. Side effects include anorexia, nausea, vomiting, and diarrhea.
6-Thioguanine: 6-Thioguanine (6-TG), a purine analog, is primarily used in the treatment of acute non lymphocytic leukemia in combination with daunorubicin and cytarabine. Like 6-MP, 6-TG is converted intracellullarly to TGMP (also called 6-thioguanylic acid) by the enzyme HGPRT. TGMP is further converted to the di- and triphosphates, thioguanosine diphosphate and thioguanosine triphosphates, which are then, inhibits the biosynthesis of purine 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.
Pharmacokinetics 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.
Adverse effects: The dose-related adverse effect is Bone marrow depression.
5-Fluorouracil: It’s (5-FU) a, a pyrimidine analog, and it has a fluorine atom stable in place of a hydrogen atom at a 5th position of the uracil ring. The fluorine atom interferes with the conversion of deoxyuridylic acid to thymidylic acid, thus depriving the cell of thymidine, one of the essential precursors for DNA synthesis. 5-FU is employed primarily in the treatment of slowly growing solid tumors.
Mechanism of action: 5-FU enters into the cell through a carrier-mediated transport system and it is converted into the corresponding de-oxynucleotides (5-flurodeoxyuridine monophosphate, which competes with deoxyuridine monophosphate for thymidylate synthase. 5-FU is also incorporated into RNA, and low levels have been detected in DNA. In the later case, a glycosylase excises the 5-FU, damaging the DNA. 5-FU produces the anticancer effect in the S phase of the cell cycle.
Resistance: Resistance is encountered when the cells have lost their ability to converts a 5-FU into its active form (5-FdUMP) or increased thymidylate synthase levels or when they have altered.
Pharmacokinetics: 5-FU is given IV because of its severe toxicity to the GI tract, 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.
Adverse effects: In addition to nausea, vomiting, diarrhea, and alopecia, severe ulceration of the oral and GI mucosa, bone marrow depression, and anorexia are frequently encountered. Capecitabine: Capecitabine is a novel, oral fluoropyrimidine carbamate. It is approved for the treatment of metastatic breast cancer that is resistant to first-line drugs and is currently also used for treatment of colorectal cancer.
Mechanism of action: After being absorbed, capecitabine undergoes a series of enzymatic reactions, the last of which is hydrolysis to 5-FU. This step is catalyzed by thymidine phosphorylase enzyme that is concentrated primarily in tumors.
Pharmacokinetics: well absorbed by oral administration. Metabolites are primarily eliminated in the urine or, in the case of CO2, it is exhaled.
Adverse effects: Toxicity in the GI tract.
Cytarabine: Cytarabine is an analog of 2'-deoxycytidine in which the natural ribose residue is replaced by D-arabinose.
Mechanism of action: 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.
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 ara-U can also cause resistance.
Pharmacokinetics: 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. Excreted in the urine.
Adverse effects: Diarrhea, nausea, vomiting and severe myelosuppression, Hepatic dysfunction, leukoencephalopathy or paralysis.
Gemcitabine: Gemcitabine is an analog of the nucleoside deoxycytidine. It is used for the first-line treatment of metastatic adenocarcinoma or locally advanced of the pancreas. It also is effective against lung cancer and several other tumors.
Mechanism of action: 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. Gemcitabine diphosphate inhibits ribonucleotide reductase, which is responsible for the generation of deoxynucleoside triphosphates required for DNA synthesis.
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.
Pharmacokinetics: Gemcitabine is infused IV. It is excreted in the urine.
Adverse effects: Nausea, alopecia, Myelosuppression, vomiting, rash, and a flu-like syndrome. Transient elevations of serum transaminases, proteinuria, and hematuria are common.
Antibiotics:
The antitumor antibiotics owe their cytotoxic action primarily to their interactions with DNA, leading to disruption of DNA function. In addition to intercalation, their abilities to inhibit topoisomerases (I and II) and produce free radicals also play a major role in their cytotoxic effect. They are cell-cycle nonspecific.
Dactinomycin: Dactinomycin is also known as actinomycin D, was the first antibiotic to find therapeutic application in tumor chemotherapy. Dactinomycin is used in combination with surgery and vincristine for the treatment of Wilms' tumor.
Mechanism of action: The drug intercalates into the minor groove of the double helix between guanine-cytosine base pairs of DNA, forming a stable dactinomycin-DNA complex. The complex interferes primarily with DNA-dependent RNA polymerase, although at high doses, dactinomycin also hinders DNA synthesis. The drug also causes single-strand breaks, possibly due to action on topoisomerase II or by generation of free radicals.
Resistance: Resistance is due to an increased efflux of the antibiotic from the cell via P glycoprotein. DNA repair may also play a role.
Pharmacokinetics: The drug, administered IV, distributes to many tissues but does not enter the CSF. The drug is minimally metabolized in the liver and excreted via the urine.
Adverse effects: Bone marrow depression, nausea, vomiting, diarrhea, stomatitis, and alopecia.
Doxorubicin and daunorubicin: These are classified under anthracycline antibiotics. Doxorubicin is the hydroxylated analog of daunorubicin. Doxorubicin is one of the most important and widely used anticancer drugs. It is used in combination with other agents for treatment of sarcomas and a variety of carcinomas, including breast and lung, as well as for treatment of acute lymphocytic leukemia and lymphomas.
Mechanism of action: The anthracyclines have three major activities that may vary with the type of cell. All three are effective in the S and G2 phases.The drugs insert nonspecifically between adjacent base pairs and bind to the sugar-phosphate backbone of DNA. This causes local uncoiling and, thus, blocks DNA and RNA synthesis. Intercalation can interfere with the topoisomerase catalyzed breakage/reunion reaction of super coiled DNA strands, causing irreparable breaks. Binding to cell membranes: This action alters the function of transport processes coupled to phosphatidylinositol activation.Generation of oxygen radicals: Cytochrome P450 reductase (present in cell nuclear membranes) catalyzes reduction of the anthracyclines to semiquinone free radicals. These in turn reduce molecular O2, producing superoxide ions and hydrogen peroxide, which mediate single-strand scission of DNA.
Pharmacokinetics: Administered by IV, because they are inactivated in the GI tract. The anthracycline antibiotics bind to plasma proteins as well as to other tissue components, where they are widely distributed. All these drugs undergo extensive hepatic metabolism. The bile is the major route of excretion.
Adverse effects: Cardio toxicity, transient bone marrow suppression, stomatitis, and GI tract disturbances. Increased skin pigmentation is also seen. Alopecia is usually severe.
Plant derivatives:
Vincristine and vinblastine: Vincristine and vinblastine are structurally related compounds derived from the plant, Vinca rosea or periwinkle. They are therefore referred to as the vinca alkaloids. They are generally administered in combination with other drugs. VX is used in the treatment of acute lymphoblastic leukemia in children, Wilms' tumor, Ewing's soft-tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, as well as some other rapidly proliferating neoplasm’s. VBL is administered with bleomycin and cisplatin for the treatment of metastatic testicular carcinoma. It is also used in the treatment of systemic Hodgkin's and non-Hodgkin's lymphomas.
Mechanism of action: VX and VBL are both cell-cycle specific and phase specific, because they block mitosis in metaphase (M phase). Their binding to the microtubular protein, tubulin, is GTP dependent and blocks the ability of tubulin to polymerize to form microtubules. Instead, paracrystalline aggregates consisting of tubulin dimers and the alkaloid drug are formed. The resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation.
Resistance: Resistant cells have been shown to have an enhanced efflux of VX, VBL, and VRB via P-glycoprotein in the cell membrane. Alterations in tubulin structure may also affect binding of the vinca alkaloids.
Pharmacokinetics: Intravenous injection of these agents leads to rapid cytotoxic effects and cell destruction. This in turn can cause hyperuricemia due to the oxidation of purines that are released from fragmenting DNA molecules, producing uric acid. The vinca alkaloids are concentrated and metabolized in the liver by the cytochrome P450 pathway. They are excreted into bile and feces. Adverse effects: Both VX and VBL have certain toxicities in common. These include phlebitis or cellulitis, if the drugs extravasate during injection, as well as vomiting, nausea, alopecia, diarrhea, and Granulocytopenia is dose limiting for VRB.
Etoposide and Teniposide: These are semi synthetic derivatives of the plant alkaloid, podophyllotoxin. They block cells in the late S to G2 phase of the cell cycle. Their major target is topoisomerase II. Binding of the drugs to the enzyme-DNA complex results in persistence of the transient, cleavable form of the complex and, thus, renders it susceptible to irreversible double-strand breaks. Resistance to topoisomerase inhibitors is conferred either by presence of the multidrug-resistant P-glycoprotein or by mutation of the enzyme. Etoposide finds its major clinical use in the treatment of oat-cell carcinoma of the lung and in combination with bleomycin and cisplatin for testicular carcinoma. Teniposide is used as a second-line agent in the treatment of acute lymphocytic leukemia. Etoposide may be administered either IV or orally, whereas teniposide is only administered IV. They are highly bound to plasma proteins and distribute throughout the body, but they enter the CSF poorly. Metabolites are converted to glucuronide and sulfate conjugates and are excreted in the urine. Dose-limiting myelosuppression (primarily leukopenia) is the major toxicity for both drugs. Leukemia may develop in patients who were treated with etoposide. Other toxicities are alopecia, anaphylactic reactions, nausea, and vomiting.
Irinotecan and topotecan: Irinotecan and topotecan are semi synthetic derivatives of an earlier, more toxic drug, camptothecin. Topotecan is employed in metastatic ovarian cancer when primary therapy has failed and also in the treatment of small-cell lung cancer. Irinotecan is used as a first-line drug together with 5-FU and leucovorin for the treatment of colon or rectal carcinoma.
Mechanism of action: These drugs are S-phase specific. They inhibit topoisomerase I, which is essential for the replication of DNA in human cells, topotecan was the first clinically useful topoisomerase I inhibitor. SN-38 (the active metabolite of irinotecan) is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain.
Resistance: Several mechanisms may explain resistance. Among them is the ability to transport the drugs out of the cell, decreased ability to convert irinotecan to the active SN-38 metabolite, or a down-regulation or mutation in topoisomerase I.
Pharmacokinetics: Topotecan and irinotecan are infused IV. Hydrolysis of the lactone ring destroys the activity of these drugs. Both the drugs and their metabolites are eliminated in the urine.
Adverse effects: Bone marrow suppression. Other hematologic complications, including thrombocytopenia and anemia, may also occur. Non hematologic effects include diarrhea, nausea, vomiting, alopecia, and headache.
Paclitaxel and docetaxel: Paclitaxel is the first member of the taxane family to be used in cancer chemotherapy. A semi synthetic paclitaxel is now available through chemical modification of a precursor found in the needles of Pacific yew species. Substitution of a side chain has resulted in docetaxel, which is the more potent of the two drugs.
Mechanism of action: Both drugs are active in the G2/M phase of the cell cycle. They bind reversibly to the I2-tubulin subunit, but unlike the vinca alkaloids, they promote polymerization and stabilization of the polymer rather than disassembly. Thus, they shift the depolymerization-polymerization process to accumulation of microtubules. The overly stable microtubules formed are nonfunctional, and chromosome desegregation does not occur. This results in death of the cell.
Resistance: Like the vinca alkaloids, resistance has been associated with the presence of amplified P-glycoprotein or a mutation in the tubulin structure.
Pharmacokinetics: These agents are infused and have similar pharmacokinetics. Both have a large volume of distribution, but neither enters the CNS. Hepatic metabolism by the cytochrome P450 system and biliary excretion are responsible for their elimination into the stool.
Adverse effects: The dose-limiting toxicity of paclitaxel and docetaxel is neutropenia. A transient, asymptomatic bradycardia is sometimes observed with paclitaxel, and fluid retention is seen with docetaxel.
L-Asparaginase: L-Asparaginase catalyzes the deamination of asparagines to aspartic acid and ammonia. The form of the enzyme used chemotherapeutically is derived from bacteria. L-Asparaginase is used to treat childhood acute lymphocytic leukemia in combination with VX and prednisone. Its mechanism of action is based on the fact that some neoplastic cells require an external source of asparagines because of their limited capacity to synthesize sufficient amounts of that amino acid to support growth and function. L-Asparaginase hydrolyzes blood asparagine and, thus, deprives the tumor cells of this amino acid, which is needed for protein synthesis. Resistance to the drug is due to increased capacity of tumor cells to synthesize asparagines. The enzyme must be administered either IV or intramuscularly, because it is destroyed by gastric enzymes. Toxicities include a range of liver abnormalities, hypersensitivity reactions (because it is a foreign protein), pancreatitis, a decrease in clotting factors, seizures, and coma due to ammonia toxicity.
Imatinib mesylate: It is used for the treatment of chronic myeloid leukemia in blast crisis, as well as GI stromal tumor. It acts as a signal transduction inhibitor, used specifically to inhibit tumor tyrosine kinase activity. A deregulated BCR-ABL kinase is present in the leukemia cells of almost every patient with chronic myeloid leukemia. Imatinib is very well absorbed orally, undergoes metabolism by the cytochrome P450 system to several compounds, of which the N-demethyl derivative is active, excretion through the feces.
Adverse effects: thrombocytopenia or neutropenia, Fluid retention and edema, hepatotoxicity, as well as nausea and vomiting.
Gefitinib: Gefitinib targets the epidermal growth factor receptor. It is approved for the treatment of lung cancer that has failed to respond to other therapy, and it is effective in 10 to 20 percent of patients with this cancer. Gefitinib is usually used as a single agent. Gefitinib is absorbed after oral administration and undergoes extensive metabolism in the liver by the cytochrome P450 enzyme CYP3A4. At least five metabolites have been identified, only one of which has significant antitumor activity. The major route of excretion of the drug and its metabolites is the feces. The most common adverse effects are nausea, diarrhea, acne, and skin rashes. A rare but potentially fatal adverse effect is interstitial lung disease, which presents as acute dyspnea with cough.
Steroid Hormones and Their Antagonists:
Hormone treatment of responsive tumors usually is only palliative, except in the case of the cytotoxic effect of glucocorticoids at higher doses (for example, prednisone) on lymphomas. Removal of hormonal stimuli from hormone-dependent tumors can be accomplished by surgery or by drugs.
Leuprolide and goserelin: Gonadotropin-releasing hormone is normally secreted by the hypothalamus and stimulates the anterior pituitary to secrete the gonadotropic hormones, luteinizing hormone (LH; the primary stimulus for the secretion of testosterone by the testes), and follicle-stimulating hormone (FSH; which stimulates the secretion of estrogen). The synthetic nonapeptides, leuprolide and goserelin, are analogs of GnRH. As GnRH agonists, they occupy the GnRH receptor in the pituitary, which leads to its desensitization and, consequently, inhibition of release of FSH and LH. Thus, both androgen and estrogen syntheses are reduced these drugs have some benefit in premenopausal women with advanced breast cancer and have largely replaced estrogens in therapy for prostate cancer. Goserelin acetate is implanted intramuscularly. Levels of androgen may initially rise but then fall to castration levels.
Adverse effects: Impotence, hot flashes, and tumor flare, are minimal compared to those experienced with estrogen treatment.
Prednisone: Prednisone is a potent, synthetic, anti-inflammatory corticosteroid with less mineralocorticoid activity than cortisol. The use of this compound in the treatment of lymphomas arose when it was observed that patients with Cushing's syndrome, which is associated with hypersecretion of cortisol, have lymphocytopenia and decreased lymphoid mass. Prednisone is primarily employed to induce remission in patients with acute lymphocytic leukemia and in the treatment of both Hodgkin's and non-Hodgkin's lymphomas.
Mechanism of action: Prednisone itself is inactive and must first be reduced to prednisolone by hydroxysteroid dehydrogenase. This steroid then binds to a receptor that triggers the production of specific proteins.
Resistance: Resistance is associated with an absence of the receptor protein or a mutation that lowers receptor affinity for the hormone. However, in some resistant cells, a receptor-hormone complex is formed, although a stage of gene expression is apparently affected.
Pharmacokinetics: Prednisone is readily absorbed orally.The latter is glucuronidated and excreted into the urine along with the parent compound.
Adverse effects: Prednisone has many of the adverse effects associated with glucocorticoids. It can predispose to infection (due to its immunosuppressant action) and to ulcers and pancreatitis. Other effects include hyperglycemia, cataract formation, glaucoma, osteoporosis, and change in mood (euphoria or psychosis).
Tamoxifen: Tamoxifen is an estrogen antagonist. It is structurally related to the synthetic estrogen diethylstilbestrol and is used for first-line therapy in the treatment of breast cancer. Tamoxifen has weak estrogenic activity, and it is classified under a selective estrogen-receptor modulator (SERM).
Mechanism of action: Tamoxifen binds to the estrogen receptor, but the complex is transcriptionally not productive. That is, the complex fails to induce estrogen-responsive genes, and RNA synthesis does not ensue. The result is depletion (down-regulation) of estrogen receptors, and the growth-promoting effects of the natural hormone and other growth factors are suppressed.
Resistance: Resistance is associated with a decreased affinity for the receptor or the presence of a dysfunctional receptor.
Pharmacokinetics: Tamoxifen is effective on oral administration. It is partially metabolized by the liver and its metabolites are excreted predominantly through the bile into the feces.
Adverse effects: Hot flashes, nausea, vomiting, skin rash, vaginal bleeding, and discharge, Hypercalcemia. Tamoxifen has the potential to cause endometrial cancer. Other toxicities include thromboembolism and effects on vision.
Aminoglutethimide: Aminoglutethimide was the first aromatase inhibitor to be identified for the treatment of metastatic breast cancer in postmenopausal women. Aminoglutethimide was shown to inhibit both the adrenal synthesis of pregnenolone (a precursor of estrogen) from cholesterol as well as the extra-adrenal synthesis. Because the drug also inhibits hydrocortisone synthesis, which evokes a compensatory rise in adrenocorticotropic hormone secretion sufficient to overwhelm the blockade of the adrenal, the drug is usually taken with hydrocortisone. Anastrozole and letrozole: The imidazole aromatase inhibitors, such as anastrozole and letrozole, are nonsteroidal. They have gained favor in the treatment of breast cancer because 1) they are more potent, 2) they do not predispose to endometrial cancer, 3) they do not need to be supplemented with hydrocortisone, 4) they are more selective than aminoglutethimide, and 5) they are devoid of the androgenic side effects that occur with the steroidal aromatase inhibitors. They are orally active and cause almost a total suppression of estrogen synthesis. They are cleared primarily by liver metabolism.
Megestrol: Megestrol acetate was formerly the progestin used most widely in treating metastatic hormone-responsive breast and endometrial neoplasm’s. It is orally effective. Other agents are usually compared to it in clinical trials. However, the aromatase inhibitors are replacing it in therapy.
Flutamide, nilutamide, and bicalutamide: Flutamide, nilutamide, and bicalutamide are synthetic, nonsteroidal antiandrogens used in the treatment of prostate cancer. They compete with the natural hormone for binding to the androgen receptor and prevent its translocation into the nucleus. Flutamide is metabolized to an active hydroxy derivative that binds to the androgen receptor. Flutamide blocks the inhibitory effects of testosterone on gonadotropin secretion, causing an increase in serum LH and testosterone levels. These antiandrogens are taken orally. These agents are cleared through the kidney.
Adverse effects: gynecomastia and GI distress and, in the case of flutamide, liver failure could occur. Nilutamide can cause visual problems.
Estrogens: Estrogens, such as ethinyl estradiol or diethylstilbestrol, had been used in the treatment of prostatic cancer. However, they have been largely replaced by the GnRH analogs because of fewer adverse effects. Estrogens inhibit the growth of prostatic tissue by blocking the production of LH, thereby decreasing the synthesis of androgens in the testis. Thus, tumors that are dependent on androgens are affected. Estrogen treatment can cause serious complications, such as thromboemboli, myocardial infarction, strokes, and Hypercalcemia. Men who are taking estrogens may experience gynecomastia and impotence.
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. The resulting hybrid cells can be individually cloned, and each clone will produce antibodies directed against a single antigen type.
Trastuzumab: 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.
Mechanism of action: 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.
Pharmacokinetics: Trastuzumab is administered IV. Trastuzumab does not penetrate the blood-brain barrier.
Adverse effects: The most serious toxicity associated with the use of trastuzumab is congestive heart failure. Other adverse effects include infusion-related fever and chills, abdominal pain, headache, nausea, dizziness, vomiting, and back pain, but these effects are well tolerated. B. Rituximab: 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 non-Hodgkin's lymphomas, but not in other bone marrow cells. Rituximab has proven to be effective in the treatment of post transplant lymphoma and in chronic lymphocytic leukemia.
Mechanism of action: Rituximab binds to the CD20 antigen on the B lymphocytes, and its Fc domain recruits immune effector functions, inducing complement and antibody-dependent, 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).
Pharmacokinetics: Rituximab is infused IV and causes a rapid depletion of B cells (both normal and malignant).
Adverse effects: Hypotension, bronchospasm, and angioedema may occur. Chills and fever frequently accompany the first infusion, 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 hyper phosphatasemia.
Cancer, chemotherapy, cancer treatment by drugs
