Chemotherapy of Malignancy After oral administration it is well absorbed It is a prodrug and converted in the blood and liver to its active form (metabolites) namely hydroxyphosphamide and aldophosphamide It is excreted in urine Adverse effects include nausea, vomiting, visual blurring, facial burning with IV administration, teratogenic effect, haemorrhagic cystitis, bone marrow depression, hyponatremia, sterility, inappropriate secretion of ADH, alopecia and increased skin pigmentation It is indicated in leukaemias, lymphogranulomatosis, lymphosarcoma, reticulum cell sarcoma, Hodgkin’s disease, multiple myeloma, retinoblastoma, carcinoma of the breast, adenocarcinoma of the ovary, inoperable solid malignancies It is used in combination with surgery, radiation and other therapeutic measures MESNA Cyclophosphamide and ifosfamide cause urothelial toxicity (haemorrhagic cystitis) which is caused by metabolite ‘acrolein’ Mesna reacts with this metabolites in the urinary tract to prevent toxicity and is used in prevention of toxicity to the urinary passage caused by oxazaphosphorins e.g ifosfamide and cyclophosphamide CHLORAMBUCIL It is a slow acting alkylating agent After oral administration, it shows adequate and reliable absorption and almost completely metabolised It is indicated in chronic lymphocytic leukaemia (drug of choice), primary 373 (Waldenstrom’s) macroglobulinaemia, advanced ovarian adenocarcinoma, breast cancer, certain forms of nonHodgkin’s lymphoma and Hodgkin’s disease Adverse effects include nausea, vomiting, pulmonary fibrosis, dermatitis, hepatotoxicity, seizures, amenorrhoea, azoospermia, peripheral neuropathy and bone marrow depression BUSULFAN After oral administration, it is well absorbed and excreted in urine as methanesulfonic acid It is mainly used in chronic myeloid leukaemia, polycythemia vera, essential thrombocythemia and myelofibrosis Adverse effects include, thrombocytopenia, amenorrhoea, azoospermia, skin pigmentation, nausea, vomiting, cataract, gynaecomastia, pulmonary fibrosis and hyperuricaemia LOMUSTINE It is rapidly absorbed from GIT after oral administration and is completely and rapidly metabolised It is indicated in Hodgkin’s disease, brain tumour, lung carcinoma, solid tumours and malignant melanoma Adverse effects include nausea, vomiting, delayed bone marrow depression (four to six weeks), leucopenia, thrombocytopenia and pulmonary fibrosis THIO-TEPA Chemically it is ethylenimine and because of high toxicity, it is rarely used Section 9/ Chemotherapy 374 ANTIMETABOLITES Antimetabolites are analogues of normal DNA components or of coenzymes involved in nucleic acid synthesis They get incorporated or competitively inhibit utilization of normal substrate to form dysfunctional nucleic acid molecules METHOTREXATE It is a broad spectrum antineoplastic drug which act as an antimetabolite of folic acid It acts by inhibiting dihydrofolate reductase It inhibits conversion of dihydrofolic acid to tetrahydrofolic which is essential for purine synthesis and amino acid interconversions It primarily affects DNA synthesis but also RNA and protein synthesis It has cell cycle specific action and kills cells in S phase It is readily absorbed from gastrointestinal tract but larger doses are absorbed incompletely, little drug is metabolised and it is excreted largely unchanged in urine Adverse effects include nausea, vomiting, diarrhoea, anaphylaxis, hepatic necrosis, fever, bone marrow depression, osteoporosis, menstrual dysfunction, cirrhosis, pulmonary infiltrates and fibrosis, renal toxicity and depigmentation lymphocyte proliferation, rheumatoid factor production and interferes with the release of inflammatory cytokines 6-MERCAPTOPURINE It is an antimetabolite antineoplastic, which being an analogue of hypoxanthine and adenine inhibits purine metabolism After oral administration absorption is incomplete and drug is metabolised in liver The active metabolites have longer half life than parent drug Adverse effects include nausea, vomiting, diarrhoea, cholestasis, bone marrow depression, pancreatitis, oral and intestinal ulcers Rarely hepatic necrosis It is used in acute leukaemia, choriocarcinoma and chronic granulocytic leukaemia FLUOROURACIL It is fluorinated analogue of pyrimidine, act by binding the enzyme thymidylate synthetase and preventing the production of basic component of DNA-thymine It is converted into 5-fluorouridine triphosphate and is incorporated into RNA where it interferes with RNA processing and function It is used in the treatment of carcinoma of breast, colon, urinary bladder, stomach liver, rectum and ovaries It is indicated in lymphoblastic leukemia and choriocarcinoma, psoriasis, adjuvant therapy of non-metastatic osteosarcoma and to reduce corticosteroid requirement in patients with severe steroid dependent asthma The major toxicity includes myelosuppression and mucositis It is also used as ‘disease modifying drug’ in rheumatoid arthritis as it reduces Cytarabine or cytosine arabinoside competitively inhibits DNA polymerase CYTARABINE Chemotherapy of Malignancy and blocks generation of cytidylic acid and is a drug of choice for acute myeloid leukaemia It is indicated in acute myelocytic leukaemia, acute lymphocytic leukaemia, chronic myeloid leukaemia (blast phase), non-Hodgkin’s lymphoma in children, treatment and maintenance of meningeal neoplasms, erythroleukaemia Adverse effects include depression of bone marrow which gives rise to leukopenia, thrombocytopenia, reticulocytopenia GI disturbances, oral and anal ulceration, hepatic and renal dysfunction and peripheral neurotoxicity with high doses CYTOTOXIC ANTIBIOTICS These drugs are obtained from various microorganisms and have antitumor activity They act by binding to double stranded DNA and interfere with its functions DACTINOMYCIN (ACTINOMYCIN D) It is a potent antitumor antibiotic isolated from Streptomyces organism It binds tightly to double stranded DNA through intercalation between adjacent guanine cytosine base pair and inhibit all forms of DNA dependent RNA synthesis It is used in choriocarcinoma, Hodgkin’s disease and Wilm’s tumour in combination with irradiation 375 DNA intercalator and it generates free radicals It is usually administered by intravenous route It does not cross blood brain barrier Adverse effects include nausea, vomiting, diarrhoea, fever, red urine (harmless), ventricular arrhythmia, severe local tissue damage on extravasation, cardiotoxicity, bone marrow depression, anorexia, stomatitis, alopecia, conjunctivitis It is indicated in GI tract carcinoma, acute myeloblastic leukaemia, bronchogenic, breast and ovarian carcinoma, soft tissue and bone sarcomas, malignant lymphoma; primary management of nonmetastatic bladder carcinoma (intravesical administration), Wilm’s tumor and neuroblastoma Epirubicin (FARMORUBICIN) is structurally similar to doxorubicin and is similarly effective in the treatment of breast cancer, lung cancer and lymphoma BLEOMYCIN It is a mixture of cytotoxic glycopeptide antibiotic isolated from a strain of Streptomyces verticillus It exerts its cytotoxic action by causing fragmentation of DNA and it generates free radicals It is usually administered by parenteral route It does not cross blood brain barrier DOXORUBICIN Adverse effects include nausea, vomiting, allergic reactions, fever, anaphylaxis, skin rash, Raynaud’s phenomenon, stomatitis, pulmonary fibrosis, hyperpigmentation, renal and hepatic toxicity It is a cytotoxic anthracycline antibiotic isolated from Streptomyces pneuceticus It is Bleomycin is used as palliative and adjuvant to surgery and radiation therapy in Adverse effects include damage of skin, alopecia, bone marrow depression, vomiting and diarrhoea Section 9/ Chemotherapy 376 testicular tumour, squamous cell carcinoma of skin, neck and head, genitourinary tract and oesophagus neoplasm, malignancy of cervix, Hodgkin’s and non Hodgkin’s lymphoma, choriocarcinoma and embryonal cell carcinoma of testis, brain tumour and glioma MITOMYCIN-C It is a highly toxic antibiotic with antitumour activity isolated from Streptomyces caespitosus It inhibits DNA synthesis and cross links DNA After oral administration the absorption is unpredictable It is metabolised in liver Adverse effects include local reaction if extravasation occurs, constipation, paralytic ileus, jaw pain, alopecia, bone marrow depression, peripheral neuropathy, inappropriate ADH secretion, shortness of breath and bronchospasm It is indicated in acute leukaemias, lymphomas, Ewing’s sarcoma, neuroblastoma, Wilm’s tumour and idiopathic thrombocytopenic purpura VINBLASTINE After oral administration it exhibits inconsistent absorption Hence it is administered by IV route and is metabolised in liver It interferes with metabolic pathways of amino acids leading from glutamic acid to the citric acid (Krebs) cycle and urea It is used in the treatment of adenocarcinoma, lymphosarcoma and seminoma It is also used in squamous cell carcinoma of cervix Vinblastine has an effect on cell energy production required for mitosis and interferes with nucleic acid synthesis Reversal of antitumour effect by glutamic acid or tryptophan has occurred Adverse effects include nausea, vomiting, alopecia, pulmonary fibrosis, bone marrow depression, sterility, amenorrhoea and renal toxicity It undergoes rapid distribution and extensive tissue binding following IV injection It is metabolised in liver VINCA ALKALOIDS The vinca alkaloids are isolated from plant Vinca rosea They are cell cycle specific and mitotic inhibitors VINCRISTINE It blocks mitosis and produces metaphase arrest by binding to microtubular protein ‘tubulin’, preventing its polymerization Adverse effects include hepatic function impairment, leucopenia, aspermia, nausea, vomiting, hypertension and alopecia It is indicated in Hodgkin’s and non Hodgkin’s lymphoma, testicular carcinoma, mycosis fungoides and Kaposi’s sarcoma VINORELBINE It is semisynthetic vinca alkaloid It interferes with microtubules, in miotic spindle fibres leading to cell cycle arrest Chemotherapy of Malignancy in metaphase It is used for the treatment of non small cell lung carcinoma, breast carcinoma, Hodgkin’s disease, ovarian carcinoma, squamous cell carcinoma of the head and neck, cervical squamous cell carcinoma, renal cell cancer and Kaposi’s sarcoma 377 It is used in the treatment of metastatic carcinoma of colon or rectum Adverse effects include vomiting, diarrhoea, abdominal discomfort, leukopenia, anemia, neutropenia, haemorrhage, insomnia and dizziness TOPOTECAN TAXANES PACLITAXEL It is an alkaloid ester derived from the western yew Taxus brevifolia It is a diterpenoid compound and is a natural product with antitumour activity It binds specifically to the β -tubulin subunit of microtubule and appears to antagonise the disassembly of this cytoskeletal protein i.e enhances polymerization of tubulin Arrest in mitosis follows The cell killing is dependent on both drug concentration and duration of cell exposure It is indicated in metastatic ovarian and breast cancer Adverse effects include bone marrow depression, hypersensitivity reactions, chest pain, bradycardia, sensory neuropathy, nausea, vomiting, diarrhoea, alopecia and impaired liver function tests Docetaxel (DOXOTEL), a related drug, used in metastatic breast cancer TOPOISOMERASE-I INHIBITORS Topotecan also inhibits topoisomerase I Adverse effects include abdominal discomfort, vomiting, diarrhoea, intestinal obstruction, nausea, stomatitis, anorexia, bone marrow suppression (primarily neutropenia, anaemia and thrombocytopenia) It is valuable in control of metastatic ovarian cancer, including cisplatinresistant neoplasms HORMONE AND HORMONE ANTAGONISTS These are not cytotoxic drugs They act by modifying the growth of hormone dependent tumours FOSFESTROL (STILBOESTROL) Fosfestrol is a synthetic non-steroidal estrogen which is activated by the enzyme acid phosphatase to produce stilboestrol Metabolism occurs primarily in the liver It is used as palliative treatment of disseminated mammary or prostatic carcinoma Adverse effects include hepatic cutaneous porphyria, perineal pain, erythema and feminising effects in man ETHINYL ESTRADIOL IRINOTECAN It inhibits topoisomerase-I, the enzyme which is involved in DNA replication It is also indicated in palliative treatment of disseminated mammary or prostatic carcinoma The detailed pharmacol- ... acid synthesis They get incorporated or competitively inhibit utilization of normal substrate to form dysfunctional nucleic acid molecules METHOTREXATE It is a broad spectrum antineoplastic drug... dihydrofolate reductase It inhibits conversion of dihydrofolic acid to tetrahydrofolic which is essential for purine synthesis and amino acid interconversions It primarily affects DNA synthesis but also... CYTARABINE Chemotherapy of Malignancy and blocks generation of cytidylic acid and is a drug of choice for acute myeloid leukaemia It is indicated in acute myelocytic leukaemia, acute lymphocytic leukaemia,