Antineoplastic agents

Antineoplastic agents

Compiled by Alok Bains

Antineoplastic agents

New and abnormal growth of cells in body parts is called neoplasm. This abnormal growth forms abnormal mass due to uncontrolled cell division or they do not die. There are two types of neoplasm: benign neoplasm and malignant neoplasm. A benign neoplasm is not considered cancer while a malignant neoplasm is considered a tumour or cancer.

Antineoplastic agents or anticancer agents control the growth of abnormal cells in the human body by killing abnormal cells. These chemotherapeutic agents will also cause harm to normal cells in the human body. Thus these drugs are more toxic. These drugs should have 100% efficacy.

Classification:

1. Alkylating agents: cyclophosphamide, ifsamidemide, mechlorethamine, chlorambucil, melphalan, busulfan, nitrosourea, lomustine

2. Antimetabolites: mercaptopurine, methotrexate, fluorouracil, cytrabine, thyoguanide, fluderbine

3. Antibiotics: doxorubicin, dacunorubacin, ibarubacin, bleomycin, dectinomycin, pilcamycin, actinomycin, metomycin

4. Natural Products: vinblastin, vincrystine, paclitaxel, epipodophyllotoxin, docetaxel

5. Hormones: corticosteroids, tamoxifen, sex steroid, estrogen, progesterone, flutemide, leuprolide.

6. Miscellaneous: cisplatin, carboplatin, procarbazine. interferon, etoposide, asparaginase.

Alkylating agents

Alkylating agents produce lethal effects on cells. They show more lethal effects on rapidly dividing cells both cancerous and healthy cells. Alkylating agents consist of six types of drugs. These are nitrogen mustards, alkyl sulfonates, nitrousoureas, ethylineimines, methylmalamine, and triazenes.

Principle of action: All Alkylating agents act by alkylation of DNA to produce a lethal effect. Inside cells, Alkylating agents form highly reactive intermediate carbonium ions. Guanine residue present in the DNA of cells is more susceptible to carbonium ions. The transfer of the alkyl group from carbonium ions to the guanine residue of DNA is called the alkylation of DNA. DNA alkylation leads to miscoding and the death of cells.

Mechlorethamine: It is a very unstable drug. Thus its solution is prepared just before intravenous administration. It is administered intravenously due to its severe local irritating effect and severe damage effect. A smaller dose is prescribed to avoid the side effects of mechlothamine.

Indications: It is mainly used to treat Hodgkin’s disease, mycosis fungoides, palliative treatment of solid tumours, lymphosarcoma, chronic leukaemias, polycythemia vera, and lung cancer.

Contraindications: Mechlorethamine immunosuppressive effects may decrease the effect of vaccines and increases the risk of infections. It is contraindicated with various vaccines such as BCG vaccine live, cholera vaccine, influenza virus vaccine, measles (rubeola) vaccine, rotavirus oral vaccine, rubella vaccine, smallpox (vaccinia) vaccine, typhoid vaccine live and yellow fever vaccine.

· Dose: Powder for injection 10mg per vial.

a. IV: 0.4 mg/kg either as a single dose or in divided doses of 0.1 to 0.2 mg/kg per day.

b. Intracavitary (intrapleural, intraperitoneal): 0.4 mg/kg

c. Intrapericardial: 0.2 mg/kg

Cyclophosphamide and ifosfamide: These are the most commonly used alkylating agent. These drugs are nitrogen mustard.

· Mechanism of action: Both are inactive compounds. They are metabolised in the liver by the enzyme cytochrome P450 system through a hydroxylation reaction. Their metabolites interact with DNA to produce cytotoxic effects.

· Indications: Broad spectrum of activity against various cancerous diseases such as Hodgkin’s disease, breast cancer, Burkitt’s lymphoma, acute leukoblastic leukaemia, retinoblastoma, neuroblastoma and myeloma. They are also used in several non-cancerous diseases like rheumatoid arthritis, nephritic syndrome, and control of organ rejection in organ transplantation.

Contraindications: Their continuous use is contraindicated in patients suffering from depressed bone marrow. They are contraindicated with phenobarbitol, succinylcholine, dexamethasone and allopurinol. Phenobarbotol and dexamethasone increase the metabolism of Cyclophosphamide and ifosamide. Succinylcholine and allopurinol decrease the metabolism of Cyclophosphamide and ifosfamide.

·Dose:

Cyclophosphamide:

1. IV (intermittent therapy): 40-50 mg/kg (400-1800 mg/m²) divided over 2-5 days; may be repeated at intervals of 2-4 weeks.

2. IV (continuous daily therapy): 60-120 mg/m²/day (1-2.5 mg/kg/day),

3. Oral (intermittent therapy): 400-1000 mg/m² divided over 4-5 days

4. Oral (continuous daily therapy): 50-100 mg/m²/day or 1-5 mg/kg/day

Ifosfamide: 1.2 g/m2 IV over at least 30 minutes daily for 5 consecutive days; repeat every 3 weeks or after recovery from hematologic toxicity

Melphalan: It is an alkylating mustard nitrogen phenylalanine derivative. 80% of melphalan is absorbed upon oral administration and 15% of melphalan is excreted unchanged in urine. The plasma half-life is about 2 hours.

· Indication: It is used to treat multiple myeloma, malignant myeloma, solid tumour, breast cancer, ovarian cancer, bronchus cancer and palliative treatment.

• Contraindications: a bad infection, hemolytic anaemia, decreased function of bone marrow, decreased blood platelets, low levels of white blood cells, inflammation of the blood vessels, hepatic disease, interstitial pneumonitis, pulmonary fibrosis, decreased kidney function, pregnancy, breastfeeding women,

• Dose: Oral dose is 6 mg daily once a day. The dose is adjusted on the basis of blood counts done after one week.

Busulphan;

Busulphan is alkylating antineoplastic agent.

· Indications: It is used to treat chronic granulocytic leukaemia, polycythemia vera, myelofibrosis and myeloid metaplasia.

· Contraindications:

· Dose: 0.8 mg per kg body weight intravenously as a two-hour infusion every six hours for four consecutive days for a total of 16 doses.

Nitrosoureas:

It is a group of drugs that act as alkylating antineoplastic agent. They are highly lipid soluble that can alkylate both DNA and RNA to act as broad-spectrum antineoplastic agent.

· Indications: Brain tumours and metastases.

· Contraindications: 150 to 200 mg/m² intravenously every 6 weeks.

· Dose: 150 to 200 mg/m² intravenously every 6 weeks.

Carmustine:

It is nitro so ureas. It is absorbed from GIT but it is preferably administered through IV route. It is quickly distributed to tissues upon intravenous administration. It is lipid soluble and can cross the blood-brain barrier to enter into CNS.

· Indications: Tumour in CNS, Hodgkin’s disease. Resistance to nitro so ureas is not reported. It is effective against dividing cells not resting cells. Resting cells can repair its DNA if damaged by nitro so ureas.

· Contraindications: It should not be administered to individuals:

- Hypersensitive to carmustine, other nitrosoureas,

- Suffering from decreased platelets, leucocytes or erythrocytes

- Renal impairment,

- Pregnancy and lactation,

- Children and adolescents.

· Dose: 150 to 200 mg/m2 intravenously every 6 weeks. in a single dose or divided into two daily injections

Lomustine

 It belongs to the group nitro so ureas. It is well absorbed from GIT, rapidly metabolised in the liver and its half-life extends from 1 day to 3 days. Metabolites are excreted in urine while the highest concentration of active drug is found in CSF. It is administered at a gap of at least 6 weeks. It is administered through the oral route. It is lipid soluble and can cross the blood-brain barrier to enter into CNS.

· Indications: It is used to treat Hodgkins disease, brain tumour, breast cancer and GIT cancer.

· Contraindications: It causes birth defects in infants. Men and women are advised to use contraceptive precautions during therapy with lomustine and for 6 months after the treatment to avoid pregnancy. It causes irreversible infertility in males. It should not be administered to pregnant and lactating women.

- Hypersensitivity lomustine or any other nitrosoureas,

- Previous failure to other nitrosoureas,

- bone marrow depression;

- renal impairment;

- Coeliac disease or wheat allergy;

- Concomitant use of yellow fever vaccine or other live vaccines

· Dose: 120 – 130 mg/m² as a single dose every six to eight weeks or as a divided dose over 3 days, e.g. 40 mg/m²/day.