ANTICANCER DRUGS DR FATAI OLUYADI USMLEINCLINED.COM 1

CELL CYCLE AND ANTICANCER THERAPY USMLEINCLINED.COM 2

CELL CYCLE SPECIFIC ANTICANCER DRUGS USMLEINCLINED.COM 3

CANCER TREATMENT OVERVIEW  Many chemotherapeutic agents target the cell cycle  The higher the growth fraction of a cancer, the more aggressive the cancer and the better the efficacy of anticancer drugs.  Drugs can be classified as cell-cycle specific and non-cell-cycle specific. USMLEINCLINED.COM 4

COMMON ADVERSE EFFECTS OF CANCER CHEMOTHERAPY  Bone Marrow toxicity: Can be reversed by growth factors (Epoietin, Oprelvekin, Filgastrim, Sargamogastrin)  Nausea and Vomiting: Mediated by central 5HT3 and Neurokinin subtype 1 receptors. Treated by 5HT3 antagonism(Ondansetron IV or PO) and Neurokinin antagonism(Aprepitant PO). Highly emetogenic cancer drug are Cisplastin, Carustine, Cyclophosphamide.  Gastrointestinal Toxicity: Mucosal ulcerations (5-FU, Methotrexate, cytarabine. Diarrhea can also occur and can be managed with Loperamide. Diarrhea is most associated with 5-FU, Capecitabine, irinotecan, Tyrosine kinase inhibitors, epithelial growth factor inhibitors  Skin Toxicity: Hyperpigmentation, alopecia, erythema, photosensitivity, General rashes and Acral erythema. Oral pyridoxine may prevent side effect. USMLEINCLINED.COM 5

OTHER METHODS OF TREATING CANCER  SURGERY  RADIATION THERAPY USMLEINCLINED.COM 6

CLASSES OF ANTICANCER DRUGS  ANTIMETABOLITES  ALKYLATING AGENTS  PLANT ALKALOIDS  ANTIBIOTICS  HORMONES  IMMUNOTHERAPY/TARGETED THERAPY USMLEINCLINED.COM 7

ANTIMETABOLITES These drugs target the S phase of the cell cycle by interfering with replication Bone marrow suppression is a common side effect There are 3 groups: FOLATE ANTAGONISTS PYRIMIDINE ANALOGS PURINE ANALOGS USMLEINCLINED.COM 8

FOLATE ANTAGONISTS  METHOTREXATE  PEMETREXED  PRALATREXATE These drugs block the Dihydrofolate reductase enzyme leading to a decrease in thymidine, adenine, and guanine nucleotides. Adverse effects include: Bone marrow suppression (leucovorin rescue) mucositis, diarrhea, pneumonitis, hepatic fibrosis, pruritic rash. NSAIDS and Penicillins increase toxicity due to reduced renal excretion. USMLEINCLINED.COM 9

PYRIMIDINE ANALOGS These drugs inhibit Thymidilate synthase.  5-FLUOROURACIL  CAPECITABINE These drugs are converted to FdUMP which inhibits the Thymidilate synthase enzyme. Adverse effects include Bone marrow suppression, Nausea and vomiting, mucositis, diarrhea, hand-foot syndrome, Neurotoxicity (cerebellum, spinal cord) USMLEINCLINED.COM 10

PYRIMIDINE ANALOGS  CYTARABINE Inhibits DNA polymerase after phosphorylation and incorporation into DNA. Adverse effects include Bone Marrow suppression, Nausea and vomiting, mucositis, diarrhea, Neurotoxicity (Cerebellar ataxia), hepatotoxicity. USMLEINCLINED.COM 11

PYRIMIDINE ANALOGS  GEMCITABINE Inhibits DNA polymerase. Also inhibits ribonucleotide reductase as a diphosphate. Adverse effects include Bone marrow suppression, Nausea and vomiting, mucositis, diarrhea, intersititial pneumonitis. USMLEINCLINED.COM 12

PURINE ANALOGS  MERCAPTOPURINE  6-THIOGUANINE Activated by the HGPRTase to monophosphate. Inhibits PRPP amidotransferase. Adverse effects include Bone marrow uppresion, Nausea and vomiting, mucositis, diarrhea, Hyperpigmentation of the skin, Immunosuppression.  Azathioprine(immunosuppressant) is a prodrug of mercaptopurine. USMLEINCLINED.COM 13

ALKYLATING AGENTS  They are non-cell cycle specific. Can work in G1, S, G2.  They cross-link DNA on one single strand or cross-linking both strands if bifunctional.  Alkylating agents are carcionogenic. Increase risk of leukemia/lymphoma. USMLEINCLINED.COM 14

ALKYLATING AGENTS NITROGEN MUSTARDS - CYCLOPHOSPHAMIDE, IFOSFAMIDE, MECHLORETHAMINE PLATINUM ANALOGS - CISPLATIN, CARBOPLATIN, OXALIPLATIN METHYLHYDRAZINES - PROCARBAZINE NITROSUREAS - CARMUSTINE, LOMUSTINE, SEMUSTINE, STREPTOZOCIN USMLEINCLINED.COM 15

NITROGEN MUSTARDS  CYCLOPHOSPHAMIDE  IFOSFAMIDE Adverse effects include Bone marrow suppression, Hemorrhagic cystitis due to acrolein accumulation. MESNA(2-mercaptoethane sulfonate sodium) is used to protect against Hemorrhagic cystitis. MECHLORETHAMINE is another Nitrogen mustard with severe Nausea and Vomiting and severe blistering in the skin, eye and mucosa as adverse effects. It also causes bone marrow suppression. USMLEINCLINED.COM 16

PLATINUM ANALOGS CISPLASTIN CARBOPLATIN OXALIPLATIN These agents are known to cause severe nausea and vomititng and giving ondansetron is recommended with the therapy. They also cause nephrotoxicity which can be reversed or prevented by administering Amifostine. The cause ototoxicity, Peripheral neuropathies, Bone marrow suppression, Hypersensitivity to platinum. Carboplatin is less toxic thn cisplastin Oxaliplatin has no nephrotoxicity and ototoxicity. USMLEINCLINED.COM 17

METHYLHYDRAZINES PROCARBAZINE Adverse effects include Bone marrow suppression, Disulfiram-like effect, Metabolite is a Monoamine oxidase inhibitor hence can cause hypertensive crisis if taken with Tyramine containing foods, TCAs and other Monoamine oxidase inhibitor. Can also cause serotonin syndrome if taken with other drus that increase serotonin concentrations in the synaptic cleft USMLEINCLINED.COM 18

NITROSUREAS  CARMUSTINE  LOMUSTINE  SEMUSTINE  STREPTOZOCIN Adverse effects include Bone marrow suppression, Nausea and vomiting, Interstitial Pneumonitis. USMLEINCLINED.COM 19

PLANT ALKALOIDS VINCA ALKALOIDS – VINCRISTINE, VINBLASTINE, VINORELBINE TAXANES – PACLITAXEL, DOCETAXEL, CABAZITAXEL CAMPTOHECIN ANALOGS – IRINOTECAN TOPOTECAN EPIPODOPHYLLOTOXIN – ETOPOSIDE, TENIPOSIDE USMLEINCLINED.COM 20

VINCA ALKALOIDS  VINBLASTINE  VINCRISTINE  VINORELBINE These drugs are M-phase specific. They work by inhibition of microtubule polymerization They arrest mitosis in the metaphase Adverse effects include Bone marrow suppression( Except for vincristine), Peripheralneuropathies, Constipation, SIADH USMLEINCLINED.COM 21

TAXANES  PACLITAXEL  DOCETAXEL  CABAZITAXEL These drugs are also M-phase specific. They work by inhibiting Microtubule depolymerization. They arrest mitosis in prophase Adverse effects include Hypersensitivity, Bone marrow suppression, Nausea and vomiting, Mucositits, diarrhea, Peripheral neuropathies USMLEINCLINED.COM 22

CAMPTOTHECIN ANALOGS  IRINOTECAN  TOPOTECAN They are S-phase specific They inhibit Topoisomerase I enzyme in DNA replication. Adverse effects include Bone marrow suppression, Nausea and vomiting, Asthenia USMLEINCLINED.COM 23

EPIPODOPHYLLOTOXINS  ETOPOSIDE  TENIPOSIDE These drugs are also S-phase specific They work by inhibiting topoisomerase II in DNA replication Adverse effects include Bone marrow suppression, Nausea and vomiting, Hypersensitivity, Hypotension USMLEINCLINED.COM 24

ANTBIOTICS These anticancer antibiotics are extracted from Streptomyces sp.  ACTINOMYCIN D – DACTINOMYCIN  ATHRACYCLINES – DAUNORUBICIN, DOXORUBICIN, EPIRUBICIN, IDARUBICIN  BLEOMYCIN USMLEINCLINED.COM 25

ACTINOMYCIN D(DACTINOMYCIN)  DACTINOMYCIN This drug works by inhibiting RNA polymerase. They bind to dsDNA and intercalates between adjacent G-C base pairs. Adverse effects include Bone marrow suppression, Nausea and vomiting, diarrhea, Hyperpigmentation of skin, Hepatotoxicity USMLEINCLINED.COM 26

ATHRACYCLINES  DAUNORUBICIN  DOXORUBICIN  EPIRUBICIN  IDARUBICIN These drugs intercalate in DNA. They form free radicals and also block topoisomerase II. Adverse effects include Bone marrow suppression, Nausea and vomiting, Mucositis, diarrhea. Red-orange urine color. Dose dependent cardiotoxicity acutely may cause arrhythmias and chronically may cause dilated cardiomyopathy and CHF due to free radical generation. Dexrazoxane prevents the cardiotoxicity by chelating iron. USMLEINCLINED.COM 27

BLEOMYCIN This drug is G2 phase specific It binds to iron and forms free radicals which forms breaks in DNA strands. Adverse effects include: Pulmonary fibrosis, Skin reaction(rash/striae, hyperpigmentation), Hypersensitivity. USMLEINCLINED.COM 28

HORMONAL THERAPY  ANTIESTROGEN THERAPY  ANTIANDROGEN THERAPY USMLEINCLINED.COM 29

ANTIESTROGEN THERAPY  SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)  SELECTIVE ESTROGEN RECEPTOR DOWN REGULATOR (SERDs)  AROMATASE INHIBITORS USMLEINCLINED.COM 30

SERMs  TAMOXIFEN  TOREMIFENE These drugs are competitive antagonists of Estrogen receptors in breast tissues and can be used to treat Breast cancers They have agonist activities in non-breast tissue (Bone, Endometrium) Adverse effects include Hot flashes, Vanginal mucosal atrophy, vaginal bleeding and discharge, endometrial hyperplasia (Increased risk of endometrial cancer), Thromboembolism. They slow progression of osteoporosis (Raloxifene is used for osteoporosis) Lowers LDL – decrease risk of Myocardial infarction USMLEINCLINED.COM 31

SERDs  FULVESTRANT Pure Estrogen receptor antagonist. Enhances degradation of estrogen receptors. Adverse effects include Nausea, Headache, Hot flashes USMLEINCLINED.COM 32

AROMATASE INHIBITORS  ANASTRAZOLE  LETROZOLE  EXEMESTANE They competitively and irreversibly inhibit Aromatase enzyme and prevent conversion of androgens to estrogen. Adverse effects include Hot flushes, Hypercholesterolemia, Osteoporosis, Joint and muscle pain. USMLEINCLINED.COM 33

ANTI-ANDROGENS FOR PROSTATE CANCER  GnRH ANALOGS  GnRH ANTAGONISTS  ANDROGEN RECEPTOR BLOCKERS USMLEINCLINED.COM 34

GNRH ANALOGS  LEUPROLIDE  GOSERELIN  TRIPTORELIN Continous pattern of administeration causes an initial surge in GnRH release (Effects usually blocked by Androgen receptor blockers). The surge is followed by Decrease in Gonadotropin and Endogenous GnRH release leading to decreased testosterone production. This is referred to as chemical castration. Adverse effects include Hot flashes, Decreased Libido, Erectile dysfunction, Gynecomatia,Osteoporosis USMLEINCLINED.COM 35

GNRH ANTAGONISTS  DEGARELIX Directly inhibits GNRH activities on the Pituitary gland and prevents LH and FSH production Adverse effects are same as GnRH analogs( Continous use ) USMLEINCLINED.COM 36

ANDROGEN RECEPTOR BLOCKERS  FLUTAMIDE  NILUTAMIDE  BICALUTAMIDE  ENZALUTAMIDE Adverse effects are same as GNRH analogs (continuous use) USMLEINCLINED.COM 37

TARGETED THERAPY  MONOCLONAL ANTIBODIES  TYROSINE KINASE INHIBITORS  MTOR INHIBITORS USMLEINCLINED.COM 38

MONOCLONAL ANTIBODIES RITUXIMAB – Against CD20 on B-cells. Used in Non Hodgkin lymphoma, CLL ALEMTUZUMAB – Against CD52. Used in CLL TRANSTUZUMAB – Against HER 2/NEU (ErbB2). Used in Breast cancer, Gastric/Gastroesophageal adenocarcinoma. CETUXIMAB – Against HER1(ErbB1). Used in metastic colorectal cancer BEVACIZUMAB – Against VEGF. Used in Metastatic colorectal cancer, Non-small cell lung cancer, ErbB2 –ve breast cancer, Metastatic renal cell carcinoma, Glioblastoma USMLEINCLINED.COM 39

MONOCLONAL ANTIBODIES Antibodies that specifically target tumor antigens and mediates damage of these tumor antigens. They mediate this killing via Antibody dependent cellular toicity, complement dependent cytotoxicity or direct induction of Apoptosis. Adverse effects include infusion related fever, rash and dyspnea and hematologic toxicities USMLEINCLINED.COM 40

TYROSINE KINASE INHIBITORS IMATINIB – Against bcr-abl, c-kit, PDGFR. Used in CML, GI stromal tumors, GEFITINIB, EROTINIB – Against ErbB1. Used in Non-small cell lung cancer, Pancreatic cancer SORAFENIB – Against Multiple receptor tyrosine kinase. Used in Renal cell, Hepatocellular and Thyroid cancers SUNITINIB – Mutiple RTKs. Used in Metastatic renal cell cancer, GI stromal tumors, Pancreatic Neuroendocrine Tumors. USMLEINCLINED.COM 41

MTOR INHIBITORS  RAPAMYCIN (SIROLIMUS) INHIBITS mTOR, a serine/threonine kinase involved in cell growth, proliferation and motility. Used in Advanced renal cell carcinoma Adverse effects include: Pneumonitis, Bone marrow suppression and Immuosuppression. USMLEINCLINED.COM 42