Antineoplastic Agents Introduction
The term neoplasm is defined as a new and diseased form of tissue growth. Benign neoplasm is not cancerous, while malignant neoplasm is cancerous. Neoplasms have been named in variety of ways. Many neoplasms have been named after their discoverers such as Wilm’s tumor, Hodgkin’s disease and Kaposi’s sarcoma. A second method of naming neoplasm is based on a histogenic classification of the tissue from which the neoplasm is derived.
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The suffix oma usually indicates a benign tumor such as adenoma (glandular epithelium) chondroma (cartilage) or osteoma (bone). Some tumor types are named according to the neuroendocrine system comprising cells that store biogenic amines in granules. The suffix – blastoma is often used to classify these malignant neoplasms. eg. Neuroblastoma (sympathetic neurons) retinoblastoma (embryonal retina).
Antineoplastic agents are the drugs used in the treatment of cancer, malignancy, tumor, carcinoma, sarcoma, leukemia etc. Cancer is a class of disease or disorder characterized by uncontrolled proliferation of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis (where cancer cells are transported through blood stream or lymphatic system). Leukemia, a cancer of the cell in the blood usually increases overproduction of leukocytes.
Two key aspects of cellular life are
- DNA synthesis and mitosis to produce new cells and
- Cell differentiation which produces specialized cells.
Normally, cells have control mechanisms to modulate these two processes by growth factors or growth inhibitors. A balance between cell growth and cell death is maintained, cell death is actively regulated by process known as “apoptosis”. Apoptosis is defined as a process of cell shrinkage, membrane blabbing and nuclear condensation.
In cancer cell, this regulatory process is aberrant; they produce over production of growth factor and avoid apoptosis which continue to multiply in an unregulated manner. The unregulated growth causes damage to DNA, resulting in mutations to genes that encode from protein controlling cell division.
Cell Cycle and Regulation
The cell cycle is divided into four phases G1 or Gap-1, G2, M and S-phase.
The G1 phase is the period when newly created cell is born. The period of time the cell remains in the G1 phase depends upon the type of cell (tumor cell or normal cell). Cells can be born in proliferated or non-proliferated state. If the cell is a proliferating cell, it will move quickly to S or synthesis phase. In this period, DNA replicates and two copies of DNA are present in the cell.
The next phase is G2 phase and cells are prepared for final cell cycle M phase or Mitosis. There are two major control points in cell cycle, G1/S phase, the cell replicates and G2/M phase, the cell divides. G1 / S phase is important in understanding cancer and cancer treatment.
During the G1 phase, a cell can take any of the three following routes:
- Cell may enter S phase.
- Cell may enter Go phase termed as quiescence.
- Cell may terminally differentiate and die.
In normal cell, the cell may proliferate, quiescent or terminally differentiate and there is no net change in the number of cells. In cancer cell, the proliferation of cell is uncontrollable and leads to increase in number of cells.
The cell cycle is controlled by a water soluble protein called growth factor and binds to glycoprotein receptors. The growth factor autocrine controls the number of cell in either proliferated or non-proliferated state and thus maintain homeostatic. Many cancer cells produce an excessive level of this growth factor.
Antineoplastic Agents Classification
Antineoplastic agents are classified as follows:
1. Alkylating Agents:
- Nitrogen mustards :
- Examples: Cyclophosphamide, Chlorambucil, Mechlorethamine, Ifosfamide, Melphalan.
- Alkyl sulfonate :
- Example: Busulfan.
- Nitroso ureas :
- Example: Carmustine, Lomustine, Semustine, Streptozocin.
- Ethylenimine :
- Example:Thiotepa.
- Methylmelamine :
- Example:Hexamethylmelamine.
- Methyl hydrazines :
- Example: Dacarbazine, Procarbazine.
- Imidazo tetrazine :
- Example: Temozolomide.
2. Antimetabolites:
- Pyrimidine analogues:
- Examples: Fluorouracil, Cytarabine, Floxuridine, Capecitabine, Gemcitabine.
- Purine analogues :
- Examples: Thioguanine, Mercaptopurine, Fludarabine, Pentostatin, Cladribine.
- Folic acid analogs:
- Example: Methotrexate, Azathioprine, Calcium folinate.
3. Antibiotics:
- Anthracyclines :
- Example: Doxorubicin, Daunorubicin, Idarubicin, Mitoxantrone, Epirubicin.
- Bleomycin :
- Example:Bleomycin sulfate.
- Mitomycin :
- Example: Mitomycin C.
- Dactinomycin :
- Example:Dactinimycin or Actinomycin D.
- Plicamycin :
- Example: Mithramycin.
4. Plant Products:
- Vinca alkaloids :
- Example: Vincristine, Vinblastine, Vinorelbine.
- Epipodophyllotoxins :
- Example: Etoposide, Teniposide.
- Taxols :
- Example: . Paclitaxel, Docetaxel.
- Enzymes:
- Example: . L-Asparaginase, Pegaspargase.
5. Hormones:
- Adernocorticosteroids:
- Example:. Prednisone.
- Progestins :
- Example: Megestrol, Hydroxy progestrone, Medroxy progestrone.
- Oestrogens :
- Example: Diethyl stilboesterol, Ethinyl oestradiol.
- Antioestrogens :
- Example: Tamoxifen, Anastrozole, Letrozole.
- Androgens :
- Example: Testosterone, Fluoxymesterone.
- Antiandrogens :
- Example: Flutamide, Bicalutamide.
- Gonadotropin-releasing hormone analog:
- Example:. Leuprorelin, Triptorelin, Goserelin.
- Immunotherapy :
- Example: Interferon a-2a, Interferon a-2b, Interferon a- n3, Aldesleukin, Diftitox, Denileukin, Bacillus Calmette-Guerin (BCG).
- Monoclonal Antibodies :
- Example: Rituximab, Gemtuzumab, Ozogamicin.
- Radiotherapeutic Agents :
- Example: Chromic phosphate P 32, Sodium phosphate P 32, Sodium iodide I 131, Strontium 89 chloride, Samarium SM 153 lexidronam.
- Cytoprotective Agents :
- Example: Mesna, Amifostine, Dexrazoxane.
- Antineoplastic Platinum Compounds:
- Example: Cisplatin, Carboplatin, Oxaliplatin.
- Tyrosine kinase Inhibitor :
- Example: Gefitinib.
- Protein kinase Inhibitor :
- Example: . Imatinib.
- Topoisomerase Inhibitor :
- Example: Topotecan.
- Miscellaneous :
- Example: Hydroxyurea, Hydroxy carbamide, Hexamethylamine, Altretamine, Gallium nitrate, Arsenic trioxide, Bexarotene, Sargramostim, Filgrastim, Porfimer sodium.
Alkylating Agents
Alkylating agents are highly electrophilic compounds which react with nucleophiles to form a strong covalent bond. It acts by transfer of alkyl group to biologically important constituents such as amino, sulfhydryl or phosphate group whose function is then impaired. Under physiological condition, alkylating agents are positively charged and they react with negative or high electron density region.
Alkylating agents are known to react with DNA, RNA and protein. Although their reaction with DNA is believed to be most important. They act by alkylating N – 7 position of guanine in DNA, which results in the formation of apurinic site. The alkylating agent appears to be most effective in G1 or S phase.
Alternating the guanine in DNA may lead to:
- Miscoding: The guanine base usually exists as keto tautomer and base pair with cytosine. Once alkylated, guanine prefers the enol tautomer and is more likely to base pair with thymine. Such miscoding, leads to an alteration in the amino acid sequence of protein which in turn leads to disruption of protein structure and function.
- Alkylating agents may also link with two guanine group on the same chain, such that the drug is attached like a limpet to the side of the DNA helix. Such an attachment would mask that portion of DNA and block access to the necessary enzymes required for DNA function.
- It may also lead to the cleavage of imidazole ring in guanine which destroys guanine.
At physiological pH, aliphatic nitrogen mustard converts into stable aziridinium ion, which once produced will reacts with nucleophilic centre in the bio-molecule.
The nitrogen mustard compound Mechlorethamine was the first alkylating agent to be used (1942). The nitrogen mustard is quite reactive agent and administered intravenously. The nitrogen atom is able to displace a chloride ion intra-molecularly to form the highly electrophilic aziridinium ion.
Aryl substituted nitrogen mustard such as Chlorambucil and amide – like phosphoramide linkages Cyclophosphamide are relatively stable to aziridinium ion formation because the aromatic ring decreases the nucleophilicity of the nitrogen atom. These stability allows it to be taken orally, where as Mechlorethamine is given intravenously.
Ethylene imines and epoxides are strained ring systems, but they do not react readily as aziridinium ion with nucleophiles.
As somewhat different type of alkylating agent is the, N-Alkyl-N-nitrosourea. Compounds of this class are unstable in aqueous solution under physiological conditions. They produce carbonium ion that can be alkylated and isocyanates that can be carbamoylated. For example, methyl nitrosourea decomposes initially to form isocyanic acid and methyl diazohydroxide. The latter species decomposes further to methyl diazonium ion and finally to methyl carbonium ion, an ultimate alkylating species.
Nitrogen Mustards
Ifosfamide (Holoxan, Isoxan)
Synthesis
ADR: Confusion, alopecia, nausea, vomiting and depression.
Dose: 1.2 to 2.5g/m2/day for 3 to 5 days. Repeat treatment cycle every 3 to 4 weeks.
Use: It is used for cell testicular cancer, ovarian and breast carcinoma and leukemia.
Cyclophosphamide (Cyphos, Oncomide)
Synthesis
Cyclophosphamide has advantage over other alkylating agent that, it is active orally and parenterally. It requires metabolic activation (prodrug).
Mechanism of Action
Bio-activation by CYP450 enzyme gives hydroxylation to an unstable carbinolamine intermediate. This undergoes non-enzymatic fragmentation to acrolein and phosphoramide mustard which act as alkylating agent.
ADR: Congestive heart failure, leucopoenia, anorexia, nausea, vomiting, alopecia, anemia, dermatitis and jaundice.
Dose: 60mg/kg daily for 2 days.
Use: It is used against multiple myeloma, chronic lymphocytic leukemia and acute leukemia of children.
Melphalan (Alkacel, Alkeran)
It is a chemotherapy agent belongs to nitrogen mustard alkylating agent. It attaches the alkyl group to the quinine base of DNA at the number 7 nitrogen atom of the imidazole ring.
Synthesis
ADR: Diarrhea, stomatitis, vomiting, hemolytic anemia, pulmonary fibrosis, vasculitis and hepatic disorders.
Dose: 150μg/kg daily in divided doses for 4 to 7 days or 6mg daily for 2 to 3 days.
Use: It is active against multiple myeloma, breast, testicular and ovarian carcinoma.
Chlorambucil (Leukeran)
Chlorambucil acts slowly, so less toxic than any other nitrogen mustard derivatives
Synthesis
ADR: GI disturbances, hepatotoxicity, skin rashes, peripheral neuropathy and pulmonary fibrosis.
Dose: 0.1 to 0.2 mg/kg bodyweight daily for 3 to 6 weeks as required.
Use: It is used in the treatment of chronic lymphocytic leukemia (CLL), macroglobulinemia, lymphosarcoma and Hodgkin’s disease.
Alkylsulfonate
Busulfan (Bucelan, Mylefan)
Synthesis
ADR: GI symptoms, anorexia, weight loss, weakness, hyper pigmentation, amenorrhea, dry skin and liver damage.
Dose: 60μg/kg daily with maintenance dose of 0.2 to 2mg daily up to maximum 4mg daily.
Use: It is used in the treatment of chronic granulocytic leukemia (CGL).
Nitroso Urea
Lomustine (Belustine, CINU)
The high lipid solubility of Lomustine allows to cross blood-brain barrier (BBB). Its mechanism of action is similar to Carmustine.
ADR: Pulmonary fibrosis, nausea, vomiting, hepatotoxicity, nephrotoxicity, stomatitis and alopecia.
Dose: 100 to 130mg/m2 as a single dose for every 6 weeks.
Use: It is used against both primary and metastatic brain tumors and also in Hodgkin’s disease.
Methyl Hydrazines
Dacarbazine (Dabaz, Daczin)
Synthesis
Mechanism of Action
It is metabolically bio-activated by CYP450. Initial demethylation to monomethyl triazenyl imidazle carboxamide (MTIC) is followed by formation of diazomethane, a potent methylating agent. It methylates the N-7 position of guanine.
ADR: Leucopoenia, thrombocytopenia, anorexia, nausea, diarrhea, vomiting, flu-like syndrome and alopecia.
Dose: 2 to 4.5mg/kg daily for 10 days repeat at 4 weeks interval.
Use: It is used in the treatment of metastatic malignant melanoma.
Antimetabolites
Antimetabolites are compounds that prevent the biosynthesis or use of normal cellular metabolite. Chemical substances which take part in cellular metabolite are called metabolites. Antimetabolites exert their action by acting as a false precursor for enzyme or by acting as a competitive antagonist for an enzyme. These drugs are usually structural analogues of normal body metabolite, derived by incorporating one or two bio-isosteric groups or other structural changes of the metabolite.
Pyrimidine Analogues
The structural modification of these metabolites may be on the pyrimidine ring. Their possible mechanisms of actions are:
- Inhibition of kinases or enzyme involved in biosynthesis of pyrimidine.
- Incorporation into DNA or RNA leading to miscoding.
- Inhibition of DNA polymerase.
Fluorouracil (5FU – CBC, Flocil)
Synthesis
Mechanism of Action
Fluorouracil is anabolized to its 2′-deoxyribose monophosphate, a potent inhibitor of thymidylate synthase, an enzyme involved in the synthesis of thymidine which is essential for the synthesis of DNA. 2′-deoxy monophosphate is also converted into fluorouridine triphosphate which is incorporated into DNA and RNA.
ADR: Leucopoenia, thrombocytopenia, stomatitis, GI ulceration, bleeding, nausea, diarrhea, vomiting and rashes.
Dose: 12mg/kg/day for 3 days and then if there is no evidence of toxicity 6mg/kg on alternate days for 3 further doses.
Use: It is effective in palliative management of carcinoma of the breast, colon, pancreas, rectum and stomach in patient who cannot be cured by surgery. It is also used in the treatment of skin and basal cell carcinomas.
Cytarabine (Aracid, Cytabin)
Cytarabine is an example of pyrimidine antimetabolite in which the sugar has been modified. It is called Cytosine arabinoside because it combines a cytosine base with an arabinose with 2′- OH group having B- configuration rather than the normal a configuration. Cytosine arabinoside is similar enough to human Cytosine deoxyribose to be incorporated into human DNA, but different that kills the cell. This mechanism is used to kill cancer cells. It is the first of a series of cancer drugs that alter the sugar component of nucleosides.
Mechanism of Action
Sequential actions of deoxycytidine kinase anabolizes Cytarabine to triphosphorylated nucleotide, which act as a competitive inhibitor of DNA polymerase, after incorporation into DNA chain, leads to miscoding. It is specific for S-phase of the cell cycle.
ADR: Dementia, GI disturbances, hepatic and renal dysfunction, neurotoxicity, rashes, oesophagitis and flu-like syndrome.
Dose: 1.5 to 3.0mg/kg for 5 to 10 days
Use: It is used for acute leukemia, chronic myelocytic leukemia, meningeal leukemia, acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL).
Capecitabine (Captabin, Xylocel)
Synthesis:
Mechanism of Action
It is a prodrug of 5′-Deoxy-5-fluorouridine. On oral administration, it is converted into 5′-Deoxy-5-fluoro cytidine by cytidine deaminase, which is in higher concentration in many tumor cells.
ADR: Diarrhea, nausea, vomiting, stomatitis, dermatitis, fatigue, pyrexia, dizziness, and head ache.
Dose: 1.25gm/m2 bid for 2 weeks followed by a one week rest period, therapy to be given in 3 weeks cycle.
Use: It is used in acute granulocytic leukemia of adult and children.
Gemcitabine (Celgem, Xtroz)
It is a synthetic pyrimidine nucleoside and Cytarabine analogue. It inhibits DNA synthesis and is active against cells in S-phase.
ADR: Bone marrow depression, renal impairment, pulmonary edema and elevation of serum transaminase.
Dose: 1gm/m2 once weekly for up to 7 weeks followed by one week rest, continue thereafter with once weekly infusion for 3 consecutive weeks.
Use: It is used to treat pancreatic, breast, bladder and ovarian cancer.
Purine Analogues
Thioguanine (6 – TG, Thionine)
It is a guanine analogue, belongs to the family of drugs called antimetabolite. It is act by integrated into DNA and RNA, which result in the inhibition of synthesis and metabolism of purine nucleotides.
ADR: Myelosuppression, nausea, vomiting and anorexia,
Dose: 2 to 3mg/kg/day in 1 to 2 divided doses for 5 to 7 days.
Use: It is an antineoplastic agent act as an antimetabolite.
Mercaptopurine (Mercapto, Purinetone)
Synthesis
Mechanism of Action
Mercaptopurine is not active until it is metabolized to phosphorylated nucleotide. The drug is converted in vivo to corresponding ribonucleotide-6-thio inosinate by the enzyme hypoxanthine-guanine phosphoribosyl transferase. The 6-thio inosinate inhibits.
- conversion of 5-phosphoribosyl pyrophosphate into 5-phosphoribosylamine involved in purine biosynthesis.
- conversion of inosinic acid to xanthylic acid.
- oxidation of inosinic acid to xanthylic acid.
Therefore the overall action of Mercaptopurine is inhibition of the denovo synthesis of purines.
ADR: Hyperuricemia, bone marrow toxicity, hypoplasia, anorexia, diarrhea, leucopenia, thrombocytopenia and crystalluria.
Dose: Initially, 2.5mg/kg daily increased to a maximum of 5mg/kg daily. Maintenance dose 1.5 to 2.5mg/kg daily.
Use: It is used in the treatment of ALL, AML and acute myelomonocytic leukemia.
Folic Acid Analogues
Methotrexate (Oncotrex, Plastomet)
It is a 4 – Amino – 4 – deoxy folic acid derivative
Synthesis
Step 1: Preparation of 2, 4 – Diamino – 6-bromomethyl pteridine
Step 2: Preparation of N- [p – (N- Methyl amino benzoyl)] glutamic acid.
Step 3: Preparation of Methotrexate
Mechanism of Action
Methotrexate and related compounds inhibit enzyme dihydrofolate reductase. Methotrexate binds stoichiometrically with dihydrofolate reductase. Folic acid antagonists kill cells by inhibiting DNA and RNA synthesis and thus it is cytotoxic during the S-phase of the cell cycle.
It therefore has a greater toxic effect on the rapidly dividing cells which replicate their DNA more frequently and thus inhibits the growth and proliferation of these noncancerous cells. Thus they are most effective in the logarithmic growth phase.
For the treatment of rheumatoid arthritis, inhibition of dihydrofolate reductase is not thought to be the main mechanism but rather the inhibition of enzymes involved in purine metabolism leading to accumulation of adenosine or inhibition of T cell activation. and suppression of intercellular adhesion molecule expression by T cells. In these cases the patients should supplement their diets with folate.
ADR: GI disturbances, ulceration of mouth, bone marrow depression, hepatotoxicity, renal failure, alopecia, ocular irritation, megaloblastic anemia, osteoporosis and arthralgia.
Dose: 15 to 30mg/day for 5 days orally.
Use: It is used against leukemia and ALL.
Calcium folinate (Covorin, Leucovorin)
It is a folic acid derivative, act by entering the cells as 5-methyl tetrahydrofolate. It stabilizes the binding of 5-dUMP and thymidylate synthetase, enhances fluorouracil activity and neutralizes the effects of Methotrexate but increases 5-Fluorouracil.
ADR: Allergic sensitization, erythema, urticaria and pyrexia.
Dose: 200mg/m2 by slow i.v injection followed by 370mg/m2 Fluorouracil i.v injection.
Use: It is useful in enhancement of cytotoxic effect in advanced colorectal cancer.
Antibiotics
Anthracycline
Anthracyclines are large and complex family of antibiotics. They occur as glycoside of the anthracyclinone. The glycosidic linkage usually involves the 7-hydroxy group of the anthracyclinone and B-anomer of a sugar with L-configurations. Anthracyclinone refers to an aglycone containing the anthraquinone chromophore with a linear hydrocarbon skeleton related to that of tetracycline sugar. Because of the conjugated anthraquinone nucleus, the anthracylines are red in color and impart a red color to the urine of the patient.
Mechanism of action
The anthraquinone nucleus of the anthracyclines intercalate with DNA, which leads to single and double stranded DNA breaks. In addition, anthraquinone is also capable of generating reactive oxygen species such as hydroxy radical (.OH) and super
oxide radical anion (0-0). These free radicals may produce destructive effect upon the cell which may damage the DNA. The generation of free radicals leads to cardio toxicity, a major side effect of anthracycline.
The recent drugs in this classification are Daunorubicin, Doxorubicin, Idarubicin and Carminomycin. Due to lack of oral activity all the anthracyclines are administered intravenously.
Daunorubicin (Daunomycin, Daunoside)
Daunorubicin is obtained by the fermentation of Streptomyces peucetius. It is a glycoside formed between daunomycinoma and L-daunosamine. Hydroxylation of Daunorubicin gives Daunorubinol an active metabolite. It intercalates DNA and inhibits tropoisomerase-II.
ADR: GI disturbances, stomatitis, alopecia and dermatological disorders.
Dose: 30 to 60mg/m2/day daily for three days.
Use: It is used in the treatment of acute lymphocytic and granulocytic leukemia.
Doxorubicin (Oncodox, Zodox)
Doxorubicin is chemically 14-Hydroxy daunorubicin obtained from the cultures of Streptomyces peucetius. It is one of the most effective antitumor agents.
ADR: Leucopenia, thrombocytopenia, nausea, vomiting, diarrhea, alopecia, head ache, bone marrow depression and cardio toxicity.
Dose: 50mg/m2 infused over 1 hr once every 4 weeks.
Use: It is used in acute lymphoblastic and myeloblastic leukemia, Wilm’s tumor, neuroblastoma, soft tissue and bone sarcomas, breast, ovarian, thyroid, gastric carcinoma, Hodgkin’s disease, malignant lymphoma and bronchogenic carcinoma.
Epirubicin (Alrubicin, Epricin)
Epirubicin is an epimeric form of Doxorubicin. The cardiac toxicity is less when compare to Doxorubicin due to the presence of 4′-hydroxy group in an equatorial position, which increases the rate glucuronidation results in faster renal clearance.
It inhibits DNA and RNA synthesis by steric obstruction after intercalating between DNA base pairs that triggers DNA cleavage by topoisomerase-II. It also inhibits DNA helicase and generates cytotoxic free radicals.
ADR: Cardio toxicity, amenorrhea, diarrhea, nausea, vomiting, fever, rash and anorexia.
Dose: 60 to 90mg/m2 as a single dose every 3 to 4 weeks
Use: It is used to treat breast cancer.
Mitoxantrone (Mitozan)
Mitoxantrone is an analogue of anthracyclins. It intercalates into DNA and inhibits DNA topoisomerase-II causing DNA strand breakage leading to decreased cell replication.
ADR: Alopecia, fever, constipation, GI bleeding, dyspnoea, fatigue and tissue necrosis.
Dose: 12mg/m2 by i.v. infusion over 5 to 15 mts.
Use: It is used in the treatment non-lymphocytic leukemia.
Bleomycin sulphate (Bleocip, Oncobleo)
Bleomycin sulfate is a mixture of cytotoxic glycopeptidase isolated from the strain of Streptomyces verticillus. The main component is Bleomycin A2 and Bleomycin B2. Natural Bleomycins occur as a copper chelates with legand provided by pyrazine, imidazole, amide and amine functional groups. Although the copper is removed from the pharmaceutical form, metal chelate is the key to antitumor activity.
Inside the cell Bleomycin forms a chelate with Fe (II) and molecular oxygen. The resulting complex may give rise to hydroxy radical and superoxide radical. These radicals degrade the DNA by reacting with it.
ADR: Fever, rash, erythema, pruritus, hyperkeratosis, hyper pigmentation and alopecia.
Dose: 15,000 IU, 3times a week or 30,000 IU twice a week.
Use: It is used for carcinoma of cervix, head and neck, larynx, penis, skin, testes, Hodgkin’s and non-Hodgkin’s lymphoma.
Mitomycin – C (Almito, Oncocin)
Mitomycin is an antitumor antibiotic isolated from Streptomyces caespitosus as blue-violet crystals. Mitomycin has three functional groups the quinone moiety, the aziridium ring system and the carbamate involved in anticancer activity. The molecule is unreactive in neutral state. After the enzymatic or chemical bio-reductive activation, followed the elimination of methanol the compound is capable to react with Nu in DNA, leading to single strand cleavage structure.
ADR: Bone marrow depression, leucopenia, thrombocytopenia, renal damage, alopecia, fever, nausea, vomiting, diarrhea, stomatitis and dermatitis.
Dose: 10 to 20mg/m2 may be repeated every 6 to 8 weeks depending on blood count.
Use: It is used in gastric and pancreatic carcinoma.
Dactinomycin (or) Actinomycin D (Cosmegen, Dacilon)
All the Actinomycins contain the same structure, a 3 Phenoxazon – 1, 9- dicarboxylic acid. This ring system is aromatic and planar and intercalate into DNA at base pair step. This interferes with its replication and transcription.
It is obtained from the fermentation of selected strains of Streptomyces parvulus. It consists of tricyclic phenoxazone ring in the quinone oxidation state and two identical polypeptide lactone appendages. The polypeptides are made up of L-proline and L- threonine plus the non-essential amino acids D-valine, sarcosine and N-methyl valine.
An example of antineoplastic actinomycin is Dactinomycin.
ADR: Cheilitis, dysphagia, pharyngitis, anorexia, nausea, vomiting, diarrhea, hepatitis and anemia.
Dose: 15μg/kg/day for 5 days/2 weeks cycle.
Use: It is used against carcinoma in testes, Ewing’s sarcoma, Trophoblastic tumor, Wilm’s tumor and Sarcoma botryoides.
Plant Products
Vinca alkaloids
The vinca alkaloids are important antitumor agents from plants. The compounds are isolated from the periwinkle of Catharanthus rosea (Vinca rosea). They are composed of two multi ringed units Vidoline and Catharanthine.
Four closely related compounds are, Vincristine, Vinblastine, Vinrosidine and Vinleurosine and semi- synthetic derivative Vinorelbine. Among them, Vincristine and
Vinblastine are important clinical agents. They block the mitosis with metaphase arrest (Antimitotic agent).
Vincristine (Alcrist, Vinstin)
ADR: Neuromuscular toxicity, bronchospasm, azoospermia, amenorrhoea, urinary dysfunction, hyperuricemia and paralytic ileus.
Dose: 25 to 75μg/kg weekly.
Use: It is effective in acute leukemia, Hodgkin’s and Non-Hodgkin’s lymphoma, Wilm’s tumor and mycosis fungoides.
Vinblastine (Cytoblastin, Vblastin)
ADR: Alopecia, diarrhea, stomatitis, anorexia, severe bone marrow depression, granulocytopenia, thrombocytopenia, hypertension, hyperuricemia, leukopenia, 8th carnial nerve damage, bone and tumour pain.
Dose: 0.1to 0.5mg/kg every 7 to 10 days.
Use: It is used in the treatment of Hodgkin’s and Non-Hodgkin’s lymphomas, breast and testis cancer.
Epipodophyllotoxins
Etoposide and Teniposide (Beposid, Lestet)
Etoposide and Teniposide are a semi- synthetic derivatives of podophyllotoxin. The podophyllotoxin are obtained as extracts of May apple plant. The significant difference between the structure of originally isolated natural product and semi- synthetic analogues involves the stereo chemical relationship between the substituents at 1, 4- position. The podophyllotoxin have cis stereo chemistry but the synthetic analogue is trans configuration.
ADR: Reversible alopecia, disturbances of liver dysfunction, peripheral neuropathy, CNS effect and hypotension.
Dose: 50 to 100mg/m2 i.v or oral for 5 days.
Use: It is effective in lung cancer and testicular cancer.
Taxols
Taxol is an extract from the bark and needles of the yew tree, Taxus brevifolia. It is a white powder and when prepared for use becomes clear, colorless liquid which is given by intravenous route only. Taxol is an irritant. It causes inflammation of the vein through which it is given. If it escapes from the vein it may cause tissue damage. Severe allergic reaction and redness or swelling may occur at the site of i.v. injection.
There is no pill form of Taxol. The amount of Taxol and the schedule that is given will receive depend on many factors, including height and weight, general health or other health problems and the type of cancer or condition being treated. It is most commonly used in treatment of cancers like breast cancer, lung cancer and ovarian cancer. It is also used to treat AIDS related Kaposi’s sarcoma.
Paclitaxel (Altaxelm, Paclitax)
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It is structured on a tetracyclic 17- carbon (heptadecane) skeleton. It contains 11 chiral centers. The active stereo isomer is (-) Paclitaxel obtained from the tree Taxus brevifolia.
It promotes microtubule formation by enhancing the action of tubulin dimmers, then by disrupting normal cell division in the late G2 mitotic phase of the cell cycle. This result in inhibition of cell replication.
ADR: Neutropenia, tachycardia, hypertension, bradycardia, rarely hepatic necrosis and encephalopathy.
Dose: 175mg/m2 by i.v infusion over 3 hrs, repeated every 3 weeks.
Use: It is used in the treatment of breast, lung, oseophagus and bladder cancers.
Docetaxel (Docetax, Doxel)
Docetaxel belongs to the taxane group of drugs. It is a semi-synthetic analogue of Paclitaxel which is obtained from the Taxus brevifolia. Docetaxel differs from Paclitaxel at two positions in its chemical structure. It has a hydroxyl functional group on carbon 10, whereas Paclitaxel has an acetate ester and a tert-butyl carbamate ester exists on the phenyl propionate side chain instead of benzyl amide in Paclitaxel. The carbon 10 functional group change causes Docetaxel to be more water soluble than Paclitaxel
It disturbs the micro tubular net work in cells. It binds to the free tubulin result in inhibition of mitosis.
ADR: Erythematous patches, nausea, vomiting, diarrhea, stomatitis, increase in hepatic transaminase, bilirubin and alkaline phosphatase.
Dose: 100mg/m2 by i.v infusion over 1 hr, repeated every 3 weeks.
Use: It is used in the treatment of head, neck, breast, lung, oseophagus and bladder cancers.
Enzymes
L-Asparaginase (Leucoginase, Oncoginase)
L-Asparaginase, Colaspse, L-Asnase, L-Asparaginase amidohydrolase, Erwinia asparaginase are an enzyme isolated from Escherichia coli and Escherichia caratovora. The mass culture are harvested and treated with ammonium sulfate to rupture the cell and then the liberated enzyme is isolated by solvent extraction and chromatography. The enzyme produced in two forms, but only one form EC-2 has antileukemic activity. The enzyme has a molecular mass of 120,000 to 141,000 daltons. The tumor cell requires external source of asparagines, the presence of the enzyme L-Asparaginase hydrolyses the amino acid and create a deficiency which is necessary for protein synthesis.
ADR: Hyperammonemia, decrease of fibrinogen and clotting factors, alteration in blood lipids, cholesterol, hypoalbuminemia and weight loss.
Dose: 1000units/kg body weight daily for 10 days following treatment with Vincristine and Prednisone.
Use: It is used to treat childhood acute lymphocytic leukemia in combination with Vincristine and Prednisone.
Hormones
Adrenocorticoids
Progestins
Megestrol (Megace)
ADR: Diarrhea, rash, gynecomastia and impotence.
Dose: 40 to 320mg daily in divided doses.
Use: It is orally active Progesterone, used as oral contraceptive. It is used to treat endometrial carcinoma and breast carcinoma.
Oestrogens
Antioestrogens
Tamoxifen (Oncomox, Tomifen)
It competitively binds to oestrogen receptors on tumors and other tissue target, decrease DNS synthesis and inhibiting oestrogen effect. It is only cytostatic rather than cytotoxic due to accumulation of cell in Go and G1 phase.
Synthesis
ADR: Hot flushes, edema, fluid retention, dry skin, vaginal bleeding, GI upset, tumor pain and flare, blurred vision, loss of acuity, increased liver enzyme, hypertriglyceridemia, thrombosis and thromboembolism.
Dose: As citrate 20mg daily as a single dose or two divided doses. Maximum dose is 40mg daily.
Use: It is a non-steroidal antiestrogenic agent. It is useful in the treatment of breast cancer in postmenopausal women.
Letrozole (Momazol, Letzol)
It competitively inhibit the aromatase enzyme system by binding to the heme group of aromatase, a cytochrome P450 enzyme which catalase conversion of androgen to oestrogen leading to inhibition of the enzyme and a significant reduction in plasma oestrogen level.
Synthesis:
ADR: Hot flushes, dyspepsia, constipation, diarrhea, anorexia, increased sweating, peripheral edema, arterial thrombosis and cerebrovascular infarction.
Dose: 2.5mg/day.
Use: It is used in the treatment of breast carcinoma, adjuvant therapy for postmenopausal women with breast cancer.
Anastrozole (Altroz, Arimidex, Armotraz)
It is a reversible Type-II non-steroidal aromatase inhibitor.
ADR: Hot flushes, vaginal dryness, vaginal bleeding, hair thinning, arthralgia, bone fracture, myalgia and abnormal liver enzyme values.
Dose: 1mg daily.
Use: It is useful in the treatment of breast cancer.
Androgens
Anti-androgens
Bicalutamide (Biprosta, Utamide)
It is a non-steroidal anti-androgen. It competes with androgen for the binding of androgen receptors, consequently blocking the action of androgen of adrenal and testicular origin thus preventing the growth of normal and malignant prostatic tissue.
ADR: Asthenia, gynaecomastia, breast tenderness, pruritis, weight gain, CV disorders, depression, jaundice and thrombocytopenia.
Dose: 150mg/day.
Use: It is useful in the treatment of prostate cancer.
Flutamide (Eulexin, Flutam)
It is also known as Flutamin. It acts directly on the target tissue either by blocking androgen uptake or by inhibiting cytoplasmic and nuclear binding of androgen.
ADR: Impotence, increased appetite, sleeps disturbances, head ache, anemia, nausea, vomiting and diarrhea. ·
Dose: 250mg tid preferably at least 3 days before gonadorelin analogue treatment.
Use: It is a non-steroidal anti-androgen used in the treatment of prostate cancer.
Gonadotropin – Releasing Hormone (GnRH) Analogue
Goserelin (Zoladex)
It is a decapeptide available in the form of injection. It is a gonadotropin releasing hormone superagonist (GnRH agonist) also known as a luteinizing releasing hormone (LRH) agonist. Its acetate is used to suppress the production of sex hormones Testosterone and Oestrogen particularly in the treatment of breast and prostate cancer.
ADR: Vaginal bleeding, arthralgia, sexual dysfunction, insomnia and breast swelling.
Dose: 3.6mg every 28 days.
Use: To treat prostate and breast cancer.
Leuprorelin (Leupride, Progtase)
It is also called Leuprolide acetate. It is a gonadotropin releasing hormone. The proper sequence present in the structure is L-Pyroglutamyl-His-Trp-Ser-Tyr-D-Leu-Leu- Arg-Pro-NHEt. It is a potent inhibitor of gonadotropin result in subsequent reduction of secretion of sex hormone.
ADR: ECG changes, head ache, breast tenderness, GI disturbances, nausea, vomiting and constipation.
Dose: 3.75mg every month given as a single i.m/s.c depot injection.
Use: To treat prostate cancer.
Triptorelin (Decapeptyl)
It is a decapeptide (pGlu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2). It decreases LH and FSH causes suppression of ovarian and testicular steroidogenesis. It is available as acetate or pamoate salt.
ADR: Head ache, hyperglycemia, sexual dysfunction in men, breast swelling, GI disturbances and increase in menstrual bleeding.
Dose: 3 or 3.75mg of depot preparation by i.m injection every 4 weeks; precede the 1st dose with 0.1mg daily for 7 days by s.c injection. 3mg for every 28days, 3.75mg for every 4 weeks, 11.25mg for 3 months.
Use: To treat advanced prostate cancer in men.
Immunotherapy
Interferons
Interferons are a family of cytokines with broad-spectrum of antiviral and anticancer activities making them biological response modifier. These are biotherapy agents, which enhances normal immune interactions with the cell in a specific or non- specific fashion. Three types of naturally occurring interferons have been found:
- Leukocyte interferons: Interferon-a produced by lymphocytes and macrophages.
- Fibroblast interferons: Interferon-ẞ produced by fibroblast, epithelial cell and macrophages.
- Immune interferons: Interferon-y synthesized by CD4+, CD8+ and natural killer lymphocytes.
Interferon-a possess complex antiviral, antineoplastic and immuno modulating activities.
Interferon – a 2a (Alferon, Intalfa)
ADR: Flu-like symptoms, lethargy, ocular side effects, hypertension, arrhythmias, change in taste and thyroid dysfunction.
Dose: 3million units, 3 times weekly for 1 week then, 9 million units 3 times weekly for 1 week then, 18 million units 3 times weekly by s.c/i.m.
Use: It is useful in the treatment of hairy cell leukemia, chronic myelogenous leukemia and multiple myeloma.
Interferon – a 2b (Shanferon, Vivaferon)
ADR: Flu-like symptoms, myelosuppression, CV problems, nephrotoxicity and hepatotoxicity.
Dose: 5 to 10million units, 3 times weekly for 4 to 6 months or 5 million units daily for 4 months.
Use: It is useful in the treatment of AIDS related Kaposi’s sarcoma, hairy cell leukemia, chronic myelogenous leukemia and multiple myeloma.
Cytoprotective Agents
Amifostine (Amfos, Cytofos)
It is a pro-drug converted to a pharmacologically active metabolite (free thiol) which selectively protects non-cancer cells from the toxic effects of other cancer therapy agents and radiation.
ADR: Hypotension during infusion, fall in systolic pressure, flushing, feeling of warmth, chills, sneezing and drowsiness.
Dose: 200mg/m2 daily, as an infusion given over 3mts, 15 to 30mts before radiotherapy.
Use: It is used to decrease the risk of kidney problem caused by treatment with a certain anticancer drug (Cisplatin).
Mesna (Mesnex, Uromitexan)
It is an organosulfur compound.
ADR: Tachycardia, GI disturbances, head ache, skin rash and yellowing of teeth on prolonged use.
Dose: The total dose of Mesna is 60% of the Ifosfamide dose and dosing schedule can be repeated on each day of Ifosfamide dose.
Use: It is used for the prophylaxis of the patient being treated with Ifosfamide or Cyclophosphamide. It is also used as mucolytic agent in the management of respiratory disorders.
Antineoplastic Platinum Compounds
Cisplatin (Cytopaltin, Plationco)
Cisplatin is a platinum complex containing two ammonia molecule and two chlorine atom in cis configuration. It modifies cell cycle by interfering with DNA structure. It acts by inhibiting DNA polymerase. It is more effective in S phase but cells are killed in all the stages.
Synthesis
ADR: Hypomagnesaemia, hypocalcaemia, hyperuricemia, peripheral neuropathy and optic neuritis.
Dose: 20mg/m2 daily for 5 days every 3 to 4 weeks.
Use: It is used in combination with Bleomycin and Vinblastine for metastatic testicular tumor.
Carboplatin (Cytocarb, Carbopa)
It is an alkylating agent, binds covalently to DNA. It modifies the cell cycle by interfering with DNA structure and function.
Synthesis
ADR: Thrombocytopenia, neutropenia, leucopenia, central neurotoxicity, peripheral neuropathic pain, ototoxicity, elevation of ALT, AST and blood urea.
Dose: when used as a single agent in previously untreated patients, 400mg/m2 by i.v infusion over 15 to 60mts on day at 4 weekly intervals and for use as a single agent in previously treated patients initiate at 360mg/m2.
Use: It is used for an advanced ovarian cancer.
Oxaliplatin (Platoxin, Xplatin)
It is a platinum containing complex similar to Cisplatin.
ADR: Grade 3 to 4 thrombocytopenia, sensory peripheral neuropathies, neurological toxicity, ototoxicity and myelosuppression.
Dose: 85mg/m2 by i.v infusion over 2 to 6 hrs every 2 weeks. fotogr
Use: It is useful in the treatment of stage-III colon cancer.
Tyrosine Kinase Inhibitor
Gefitinib (Geftib, Gefonib)
ADR: Hyperuricemia, peripheral neuropathy and optic neuritis.
Dose: Up to 250mg/day.
Use: It is useful in the treatment of advanced non-small cell lung cancer.
Protein Kinase Inhibitor
Imatinib (Gleevec, Shantinib)
ADR: Fluid retention or edema, nausea and vomiting.
Dose: 400mg/day.
Use: It is used to treat chronic myelocytic leukemia.
Topoisomerase Inhibitors
Topotecan (Cantop)
ADR: Neutropenia, thrombocytopenia and anemia.
Dose: 1.5 mg/m2/day over 30mts daily for 5 consecutive days starting on day lofa 21 day cycle.
Use: It is used to treat ovarian, small cell lung cancer and colon cancer.
Miscellaneous
Filgrastim (Grafeel)
It is a granulocyte colony stimulating factor (G-CSF) analogue used to stimulate the proliferation and differentiation of granulocytes. It is produced by recombinant DNA technology. It stimulates the development of granulocytes to increase both migration and cytotoxicity.
ADR: Muscular pain, bone pain, anemia, head ache, diarrhea, urinary abnormalities and exacerbation of rheumatoid arthritis.
Dose: 12μg/kg body weight daily in single or divided dose.
Use: It is used to treat neutropenia. It is also used to increase the number of hematopoietic stem cells in the blood.
Hydroxy carbamide (Cytodrox, Neodrea)
It causes inhibition of DNA synthesis during the S-phase of cell division by acting as a ribonucleotide reductase inhibitor result in cell death.
ADR: GI disturbances, renal impairment, pulmonary edema, head ache, dizziness, drowsiness and convulsion.
Dose: 20 to 30mg/kg/day in single dose.
Use: It is a cytotoxic agent used in the treatment of cancer.
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