Anticancer Drugs

Introduction to Anticancer

  • The anticancer drugs either kill cancer cells or modify their growth — but, selectivity of these drugs limited — damages normal cells too — highly toxic
  • No Treatment: Before 1940 (Nitrogen mustard)
  • Surgery: before 1955
  • Radiotherapy: 1955 — 1965
  • Chemotherapy: after 1945
  • Immunotherapy, Hormone therapy , stem cell transplant and Gene therapy
  • Insensitive tumors but life may or may not be prolonged – Cancer esophagus, cancer stomach, sq. cell carcinoma of lung, melanoma, pancreatic cancer, myeloma, colorectal cancer
  • Adjuvant therapy: One of the main basis of treatment now for mopping up of residual cancer cells including metastases after Surgery, Radiation and immunotherapy etc.
    • Routinely used now
    • Mainly in solid tumours ~ combined modality approach
    • Breast, lung, colonic cancers

Phases of Cell Cycle

  • Gl – primary growth phase
  • S – synthesis; DNA replicated
  • G2 – secondary growth phase
  • collectively these 3 stages are called interphase
  • M- mitosis
  • C-cytokinesis

Cytotoxic drugs

  • Alkalyting agent
    • Nitrogen Mustard: Mechlorethamine, Cyclophosphamide, lfosfamide.
    • Ethylenimine: Thio- TEPA
    • Alkyl Sulphonate: Busulfan
    • Nitrosourea: Carmustine, Lomustine
    • Triazine: Dacarbazine
    • Methylhydrazine: Procarbazine
  • Platinum complexes:
    • Cisplatin, carboplatin, Oxaliplatin
  • Antimetabolites:
    • Folate antagonist: Methotrexate (Mtx), Pemetrexed
    • Purine antagonist: 6-Mercaptopurine (6-MP), 6-Thioguanine (6-TG), Azathioprine
    • Pyrimidine antagonist: 5-Fluorouracil, Capecitabine, cytarabine
  • Microtubule damaging:
    • Vincristine, vinblastin Paclitaxel, docetaxel, Estramustine
  • Topoismerase-1 inhibitor:
    • Topotecan, irinotecan
  • Topoismerase-2 inhibitor: Etoposide
  • Antibiotic:
    • Bleomycin, Mitomycin C, Actinomycin D (dactinomycin), Doxorubicin, Daunorubicin, Epirubicin,
      Mitoxantrone.
  • Miscellaneous: Hydroxyurea, L-asparginase, Tretinoin, Arsenic trioxide

HORMONAL DRUGS

  • Glucocorticoids: prednisolone.
  • Estrogens and estrogen receptor modulators:
    • fosfestrol,
    • Estrogen receptor down regulators: Fulvestrant
    • SERM-tamoxifene, Toremifene
  • Aromatase inhibitor: Letrozole, anastrazole, Exemestane
  • Androgen antagonists: Flutamide, Bicalutamide
  • 5-alpha reductase inhibitors: Finasteride, Dutasteride
  • Progestins: Hydroxyprogesterone acetate
  • GnRH analogues: Nafarelin, Triptorelin, Leuprorelin

GENERAL TOXICITIES (Anticancer Drugs)

  • Bone marrow depression: Agranulocytopenia, thrombocytopenia and aplastic anaemia etc. — Infection and Bleeding
  • Lymphoreticular system: Lymphocytopenia and inhibition of lymphocyte function — suppression of CMI & humoral immunity
    • Epithelial damage -> susceptibility to infections
    • Fungi — Candida; Viruses — Herpes zoster and CMV; Toxoplasma and Pneumocystis jiroveci
  • GIT: Diarrhoea, shedding of mucosa, haemorrhage, Nausea, vomiting — CTZ direct stimulation and generation of emetic impulses/mediator from Upper GIT
  • Oral cavity: Buccal mucosa – High epithelial turnover stomatitis. Lowered immunity -> increased oral infections. Xerostomia — dental carries, Bleeding of gums
  • Skin: alopecia Dermatitis
  • Gonads: oligospermia, impotence, amenorrhea and infertility
  • Foetus: Abortion, fetal death and teratogenicity
  • Carcinogenicity: leukaemias and lymphomas
  • Hyperuricaemia: Uric acid produced d/t massive cell destruction – Acute renal failure, gout and lithiasis
  • Specific toxicities: Neuropathy, cardiomyopathy, cystitis etc

Alkylating agents (Anticancer Drugs)

  • Produce highly feactive carbonium ion intermediate — transfer alkyl group to cellular macromolecules
  • Alkylation results in cross linking/abnormal base pairing/scission of DNA strands.
  • Radiomimetic actions — like ionizing radiation
  • Non specific action on cell stages
  • Some — CNS stimulant and cholinergic properties

Priatinum compounds — cisplatin, carboplatin, oxaliplatin

  • Hydrolyzed intracellularly to a highly reactive moiety — causes cross linking of DNA – N7 of guanine residues
  • Also reacts with —SH of cytoplasmic and duclear proteins
  • T1/2 = 72 hours
  • Uses: Metastatic testicular and ovarian tumours — also in lung, bladder, esophageal, hepatic, gastric etc. solid tumours
  • ADRs: Highly emetic, renal impairment — hydration required;
    • Carboplatin – 2°4 generation, better tolerated, Ovarian Ca, Head & neck, lung, breast Ca & Seminoma
    • Oxaliplatin — 3 generation, Resistant cancers – Colorectal Ca.Acute neuropathy.

Antimetabolites (Anticancer Drugs)

  • Antimetabolites are S phase-specific drugs that are structural analogues of DNA components or essential metabolites
  • They competitively inhibit utilization of normal substrate or get incorporated forming dysfunctional macromolecules and interfere with DNA synthesis
  • Myelosuppression is the dose-limiting toxicity for all drugs in this class

Methotrexate — Folate Antagonist

  • The structures of MTX and folic acid are similar
  • MIX is actively transported into manimalian cells and enters cell by Folate carrier — converts to more active polyglutamate form (FPGS)
  • MTX inhibits dihydrofolate reductase enzyme that normally converts dihydro folic acid to tetrahydrofolate required for one carbon atom transfer reactions in de novo purine synthesis and amino acid interconversion
  • Enzyme inhibition — pseudoirreversible (50,000 times higher affinity than normal substrate)
  • Additionally, also inhibits thymidylate synthase — DNA synthesis inhibition — RNA and protein also suffers

Methotrexate — ADR

  • Low doses — bone marrow toxicity, megaloblastic anaemia; high doses – pancytopenia
  • GIT- Mucositis, diarrhoea and desquamation and bleeding
  • Toxicity not reduced by Folic acid as it is not converted to active coenzyme form
  • Leucovorin rescue (folinic acid rescue): Leucovorin (Folinic acid) is directly converted to NS N10 Methylene tetrahydrofolic acid – production of DNA cellular protein in spite of presence of MTX
    • Used to rescue bone marrow and GIT mucosal cells
    • Permits higher doses
  • Indications:
    • Choriocarinoma — 15-30 mg/day for 5 days
    • Maintenance of remission of Acute lymphatic leukemia in children but not good for inducing remission
    • Tumors of head and neck, NHL, breast and bladder cancers
    • Immunosuppressant property- RA, Psoriasis, autoimmune disorders
  • Resistance: Reduction of affinity of DHFR to MTX, diminished entry of MTX into cancer cells and over production of DHFR enzyme
  • Pemetrexed: Newer congener of Mtx – targets thymidylate synthase – fess interference with DHFRase; Painful itchy rashes – hand foot syndrome

Purine Antagonists — GMP, 6TG, Azathioprine

  • 6-MP and 6-TG – Converted to corresponding monoribonucleotides — inhibits conversion of inosine monophosphate to adenine and guanine nucleotides -> RNA/DNA synthesis inhibited
  • Get incorporated to RNA and DNA & make them dysfunctional
  • Azathioprine : prodrug — selective uptake in immune cells & cellular conversion to 6-MP -> further synthesized to nucleic acid inhibitory neucleotides -> immunosuppressant action, suppress CMIl
  • Kinetics: AZA and 6-MP – Metabolized by xanthine oxidase (inhibited by allopLrinol) and allopurinol dose has to be adjusted to 1/2 or 1/4th
  • 6-TG is not substrate for xanthine oxidase, dose not decreased with allopurinol.
  • 6-MP also metabolized by methylation by thiopurine methyl transferase (TPMT) — genetic deficiency of TPMT — toxicity
  • Over expression of TPMT — resistance to 6-MP
  • ADRs: all cause BM depression, nausea vomiting with 6-MP, reversible jaundice and hyperuricaemia
  • Uses: Childhood acute leukaemia, choriocarcinoma, solid tumours , both to induce remission and 6-MP to maintain
  • AZP- Autoimmune ds- RA, UC, Organ transplantation

Pyrimidine Antagonists – 5 FU

  • Fluorouracil is an analogue of thymidine
  • Converted to corresponding nucleotide – 5-fluoro-2deoxy-uridine monophosphate (5- FdUMP) — forms covalent ternary complex with thymidylate synthase (TS) — irreversible inhibition of Thymidylate Synthase
  • Blocks conversion of (UMP to dTMP — failure of DNA synthesis due to non availability of thymidylate
  • Thymidine can partially reverse 5-FU toxicity
  • 2nd mechanism: 5-FU itself gets incorporated to RNA – interferes RNA synthesis
  • Kinetics: Used IV — metabolized by dihydropyrimiding dehydrogenase (DPD) — plasma half-life — 15-20 minutes
  • Genetic deficiency of DPD — severe 5-FU toxicity
  • ADRs: BM and GIT myelosuppression – mucositis, diarrhoea, nausea, vomiting and peripheral neuropathy (hand foot syndrome)
  • Uses: Solid malignancies — especially colon, rectum, stomach, pancreas, liver, urinary bladder and Head & Neck

Antitubulins — Vinca alkaloids (Anticancer Drugs)

  • Cell cycle specific — mitotic inhibitors
    • Binds to tubulin protein — prevents its polymerization & assembly of microtubules — cause disruption of mitotic spindle and interfere with cytoskeletal function
    • Chromosomes fail to move apart during mitosis — metaphase arrest
  • Vincristine — inducing remission of childhood ALL
    • Also AML, WT, HD, Ewings sarcoma, Neuroblastoma, Lung CA
    • ADR: Neuropathy and alopecia, paralytic ileus, postural hypotension, urinary retention, seizures
  • Vinblastine — With other drugs in HD, Kaposi sarcoma, NHL, neuroblastoma, breast and testicular cancer.
    • ADR: BM depression common

Antitubulins — Taxanes (Anticancer Drugs)

  • Taxanes — Western yew tree
    • Binds to B-tubulin and enhances its polymerization — microtubules are stabilized and depolymerization is prevented
    • Stability results in inhibition of normal reorganization of the microtubule network for mitotic function – Abnormal microtubules are formed
  • Paclitaxel — Metastatic ovarian and breast carcinoma — after failure of 1st line therapy & relapse cases
  • Also in head & neck, small cell lung cancer, esophageal adenocarcinoma, refarctory prostate CA, AIDS related Kaposi sarcoma.
  • ADR: Myelosupression, “stocking and gloves” neuropathy

Topoisomerase 1 and 2 inhibitors (Anticancer Drugs)

  • Topoisomerase 1 enzyme cut one of the 2 strands of double stranded DNA, relax the strand and reanneal them.
  • Topoisomerase 2 cut both strands of DNA helix simultaneously to manage the tangles and prevent supercoiling
  • Topotecan, Irinotecan: Acts on Topoisomerase 1 enzyme — causes single strand breaks in DNA.
    • DNA damaged during replication, acts in S phase, arrest cell cycle in G2 phase
    • Used in metastatic resistant carcinoma of ovary and lung .
    • ADR: BM suppression, neutropenia
  • Etoposide: Topoisomerase-2 inhibitor
    • Topoisomerase -2 inhibition causes DNA breaks in G2 Phase & also prevents resealing.
    • Used in testicular and lung cancers

ANTHRACYCLINE ANTIBIOTICS

  • Daunorubicin: Used in acute myeloid and lymphoblastic leukaemia
  • Doxorubicin: Effective in many solid tumours — breast, lung, sarcoma, thyroid, ovary, bladder
  • MOA: Intercalate between DNA strands — block DNA and RNA synthesis; also strand breakage of DNA & generation of free radicals
  • Toxicity: Cardiotoxicity — arrhythmia and hypotension, also CHF
  • Also mutagenic and carcinogenic

Monoclonal antibodies

  • Malignant cells express certain specific antigens on their surface to which these MAbs are directed
  • They kill tatget cell by direct signalling of apoptosis, or antibody dependent cellular cytotoxicity, or complement dependent cytotoxicity
  • They can be naked/unarmed or armed carrying immunotoxins, radioactive isotope (radiopharmaceutical)
  • Rituximab – B cel! lymphoma,Non-hodgkin’s lymphoma, CLL, Autoimmune ds
  • Alemtuzumab – Low grade lymphomas, CLL
  • Trastuzumab – HER 2/neu Breast Ca. Can cause cardiotoxicity
  • Cetuximab & Panitumumab– EGFR-positive metastatic colorectal carcinoma.
  • Bevacizumab – VEGF Metastatic colorectal ca. Combined with 5-FU

Types of Monoclonal antibodies

Toxicity countering

  • Folinic acid rescue — Mtx (adm of > 100 fold dose of Mtx)
  • Mesna (sodium-2-mercaptoethane sulfonate) administration and irrigation by acetylcysteine — detoxify toxic metabolites of cyclophosphamide & Ifosphamide
  • Ondansetron : Vomiting
  • Amifostine (organic thiophosphate) – on activation acts as cytoprotective (cisplatin-neuro/sephretoxicty)
  • Hyperurecaemia: uricosuric agents like allopurinol, alkalization of urine and plenty of fluid
  • Hypercalcaemia: IV fluid & Bisphosphonates
  • Platelet and granulocyte transfusion: to prevent bleeding and infection
  • Granulocyte colony stimulating factors (GM-CSF/G-CSF) — recovery of granulocytopenia
    (myelosupression)

Other Pharmacology Notes :-

General Anaesthetics

Hypnotics – Sedative

Depression

Antiparkinsonian Drugs

Alzheimer’s Disease

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