anticancer

• Anticancer drugs either kill cancer cells or modify their growth
• In malignant diseases, drugs are used with the aim of:

  • Cure or prolonged remission
  • Palliation: Shrinkage of evident tumor, alleviation of symptoms and life prolongation
  • Adjuvant chemotherapy: to mop up any residual malignant cells after surgery or radiotherapy
• Cell-cycle specificity of drugs
• Drugs are usually administered on the basis of body surface area
• Pharmacologic sanctuaries: Leukemic or other tumor cells find sanctuary in tissues eg. CNS, patient may require irradiation or intrathecal administration of drugs
• Combination chemotherapy is more successful than single-drug treatment
• Advantages of drug combinations:

  • Provide maximal cell killing
  • Delay or prevent the development of resistant cell lines
• General toxicity of cytotoxic drugs
• Bone marrow toxicity: Granulocytopenia, agranulocytosis, thrombocytopenia, aplastic anemia, infection and bleeding

  • GIT toxicity: Stomatitis, diarrhea, shedding of mucosa, hemorrhages, nausea & vomiting
  • Skin toxicity: alopecia
  • Foetal toxicity: abortion, fetal death, teratogenesis
  • Gonadal toxicity: Male- oligozoospermia & impotence, Female- Inhibition of ovulation, amenorrhoea
  • Carcinogenicity: secondary cancers
  • Hyperuricemia: secondary to massive cell destruction
• ALKYLATING AGENTS

  • Produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules
  • Position 7 of guanine residues in DNA is susceptible
  • Cell cycle non-specific
• Mechlorethamine:

  • The first nitrogen mustard
  • Highly reactive and local vesicant: given only by i.v. route
  • Produces acute effects like NV and haemodynamic changes
• Cyclophosphamide:

  • Produce few acute effects & is not locally damaging
  • Transformed to active metabolites in the liver
  • Has prominent immunosuppressant property
  • Cause alopecia and cystitis
• Ifosfamide:

  • Congener for cyclophosphamide with a longer t ½
  • Has found utility in various carcinomas and lymphomas
  • Hemorrhagic cystitis is the dose-limiting toxicity, reduced by Mesna
  • Mesna is a-SH compound, excreted in urine
  • Causes less alopecia and is less emetogenic than cyclophosphamide
• Chlorambucil:

  • Specially active on lymphoid tissue
  • Drug of choice for long-term maintenance therapy for chronic leukemia; Hodgkin’s disease
  • Has some immunosuppressant property
• Melphalan:

  • Effective in multiple myeloma
  • Bone marrow depression is the most important toxicity
• Busulfan:

  • Specific for myeloid elements: Granulocyte precursors being most sensitive
  • Hyperuricemia is common, sterility
  • Pulmonary fibrosis is a specific adverse effect
  • Drug of choice for chronic myeloid leukemia
• Nitrosoureas: Carmustine, Lomustine

  • Highly lipid-soluble alkylating agents with a wide range of antitumor activity
  • Cross BBB: effective in brain tumors
  • ADR: Nausea, vomiting, CNS effects, delayed bone marrow depression, visceral fibrosis, renal damage
  • Streptozocin: a derivative of nitrosourea used in pancreatic islet cell carcinoma
• ANTIMETABOLITES

  • Folate antagonist: Methotrexate (Mtx)
  • Inhibits dihydrofolate reductase
  • Has cell cycle-specific action- kills cells in S-phase
  • Exerts major toxicity on bone marrow
• Methotrexate:

  • Curative in choriocarcinoma
  • Used to maintain remission in children with acute leukemia
  • Useful in rheumatoid arthritis, psoriasis, and as an immunosuppressant
• Purine Antagonists

  • Mercaptopurine (6-MP) and Thioguanine (6-TG)
  • Mechanism: They are converted in the body to monoribonucleotides, which inhibit the conversion of inosine monophosphate (IMP) to adenine & guanine nucleotide
  • Clinical use: Acute leukemia, Choriocarcinoma, and some solid tumors
• Azathioprine:

  • Has a marked effect on T-lymphocytes
  • Metabolized by xanthine oxidase
  • Hyperuricemia occurs with both 6-MP & 6-TG
  • Allopurinol reduces it
• Pyrimidine antagonists

  • Pyrimidine analogues: have application as antineoplastic, antifungal, and antipsoriatic agents
  • Fluorouracil (5-FU)
  • Blocks the conversion of dUMP to dTMP
  • Used for many solid tumors (breast, colon, urinary bladder, liver)
• VINCA ALKALOIDS

  • Mechanism: mitotic inhibitors
  • Inhibit microtubular formation
  • Chromosomes fail to move apart during mitosis: metaphase arrest occurs
  • Cell cycle specific & act in the mitotic phase
• Vincristine:

  • Useful for inducing remission in childhood acute leukemia
  • Prominent ADR: peripheral neuropathy & alopecia
  • Bone marrow depression is minimal
• Vinblastine:

  • Used with other drugs in Hodgkin’s disease & testicular carcinoma
  • Bone marrow depression is more prominent
• TAXANES

  • Paclitaxel
  • Mechanism: Enhances polymerization of tubulin
  • Indicated in metastasis ovarian and breast carcinoma
• Docetaxel:

  • Potent congener of paclitaxel
  • Effective in breast & ovarian cancer refractory to first-line drugs
  • Toxicity: Neutropenia (major), Neuropathy (less frequent), Arrhythmia, fall in BP, and heart failure
• EPIPODOPHYLLOTOXINS

  • Etoposide
  • Semisynthetic derivative of podophyllotoxin
  • Affect DNA topoisomerase II function
  • Primarily used in testicular tumors, lung cancer, Hodgkin’s, and other lymphomas
• CAMPTOTHECIN ANALOGUES

  • Topotecan:
  • Used in metastatic carcinoma of ovary and small cell lung cancer
  • Major toxicity: bone marrow depression
• Irinotecan:

  • Indicated in metastatic/advanced colorectal carcinoma, cancer lung/cervix/ovary, etc.
  • Toxicity: diarrhea, neutropenia, thrombocytopenia, hemorrhage, body ache, and weakness
• ANTIBIOTICS

  • Actinomycin D (Dactinomycin)
  • Efficacious in Wilm’s tumor and rhabdomyosarcoma
  • Prominent adverse effects: vomiting, stomatitis, erythema, desquamation of skin, alopecia, and bone marrow depression
• Daunorubicin, Doxorubicin:

  • Mechanism: breaks DNA strands by inhibiting topoisomerase II, and generating quinine type free radicals
  • Maximum action is exerted at S-phase, other phases are also affected
  • Both produced cardiotoxicity (ECG changes)
• Mitoxantrane:

  • Analogue of doxorubicin with lower cardiotoxicity
  • Clinical use: Hormone refractory prostate cancer
  • Bleomycin:
  • Effective in squamous cell carcinoma of skin, head & neck, GI tract & esophagus, and testicular tumor also useful in Hodgkin’s lymphoma
  • Mucocutaneous toxicity & pulmonary fibrosis
  • Mitomycin C:
  • Highly toxic drug used only in resistant cancers of stomach, colon, rectum, cervix, bladder, etc
• MISCELLANEOUS CYTOTOXIC DRUGS

  • Hydroxyurea
  • Blocks conversion of ribonucleotide to deoxyribonucleotide
  • Interferes with DNA synthesis, S-phase specific action
  • Used in CML, psoriasis, polycythemia vera & some solid tumors
• Procarbazine (prodrug):

  • Depolymerizes DNA & causes chromosomal damage to DNA
  • Component of MOPP regimen for Hodgkin’s disease
  • It is a weak MAO inhibitor
  • With alcohol: Disulfiram-like reaction
• 1. asparaginase

  • Convert L-asparagine (Asn) to L-aspartic acid and ammonia
  • Used in acute lymphocytic leukemia
  • No leucopenia, alopecia, or mucosal damage
• Cisplatin:

  • Produce highly reactive moiety which causes cross-linking of DNA
  • Effective in metastatic testicular and ovarian carcinoma
  • It is an emetic drug, causes renal impairment
  • Carboplatin:
  • Less reactive second-generation platinum compound; better tolerated
• HORMONES

  • Not cytotoxic; modify growth of hormone-dependent tumors
• Glucocorticoids:

  • Cushing syndrome  marked lymphocytopenic action/decrease lymphoid mass
  • Primarily used in acute childhood leukemia and lymphomas
  • Potentiate the antiemetic action of ondansetron/metoclopramide
  • Prednisolone/dexamethasone are most commonly used
  • ADR: in high dose causes hypercorticism
• Ostrogens: Stilbestrol

  • Produce result in carcinoma prostate, which is an androgen-dependent tumor
  • Relapse occurs as hormone dependence is gradually lost, but life is prolonged
  • Antiestrogen: Tamoxifen