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ANTICANCER DRUGSDR FATAI OLUYADI

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CELL CYCLE AND ANTICANCER THERAPY

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CELL CYCLE SPECIFIC ANTICANCER DRUGS

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CANCER TREATMENT OVERVIEWMany chemotherapeutic agents target the cell cycleThe 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.

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COMMON ADVERSE EFFECTS OF CANCER CHEMOTHERAPYBone 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 inhibitorsSkin Toxicity: Hyperpigmentation, alopecia, erythema, photosensitivity, General rashes and Acral erythema. Oral pyridoxine may prevent side effect.

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OTHER METHODS OF TREATING CANCERSURGERYRADIATION THERAPY

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CLASSES OF ANTICANCER DRUGS ANTIMETABOLITESALKYLATING AGENTSPLANT ALKALOIDSANTIBIOTICSHORMONESIMMUNOTHERAPY/TARGETED THERAPY

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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

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FOLATE ANTAGONISTSMETHOTREXATEPEMETREXEDPRALATREXATE

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.

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PYRIMIDINE ANALOGS These drugs inhibit Thymidilate synthase. 5-FLUOROURACILCAPECITABINE

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)

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PYRIMIDINE ANALOGSCYTARABINE

Inhibits DNA polymerase after phosphorylation and incorporation into DNA.

Adverse effects include Bone Marrow suppression, Nausea and vomiting, mucositis, diarrhea, Neurotoxicity (Cerebellar ataxia), hepatotoxicity.


PYRIMIDINE ANALOGSGEMCITABINE

Inhibits DNA polymerase. Also inhibits ribonucleotide reductase as a diphosphate.

Adverse effects include Bone marrow suppression, Nausea and vomiting, mucositis, diarrhea, intersititial pneumonitis.


PURINE ANALOGSMERCAPTOPURINE6-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.


ALKYLATING AGENTSThey 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.


ALKYLATING AGENTS NITROGEN MUSTARDS - CYCLOPHOSPHAMIDE, IFOSFAMIDE, MECHLORETHAMINE

PLATINUM ANALOGS - CISPLATIN, CARBOPLATIN, OXALIPLATIN

METHYLHYDRAZINES - PROCARBAZINE

NITROSUREAS - CARMUSTINE, LOMUSTINE, SEMUSTINE, STREPTOZOCIN


NITROGEN MUSTARDSCYCLOPHOSPHAMIDEIFOSFAMIDE

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.


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.


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


NITROSUREASCARMUSTINE LOMUSTINESEMUSTINESTREPTOZOCIN

Adverse effects include Bone marrow suppression, Nausea and vomiting, Interstitial Pneumonitis.


PLANT ALKALOIDS VINCA ALKALOIDS – VINCRISTINE, VINBLASTINE, VINORELBINE

TAXANES – PACLITAXEL, DOCETAXEL, CABAZITAXEL

CAMPTOHECIN ANALOGS – IRINOTECAN TOPOTECAN

EPIPODOPHYLLOTOXIN – ETOPOSIDE, TENIPOSIDE


VINCA ALKALOIDSVINBLASTINEVINCRISTINEVINORELBINE

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


TAXANESPACLITAXELDOCETAXELCABAZITAXEL

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


CAMPTOTHECIN ANALOGSIRINOTECANTOPOTECAN

They are S-phase specific

They inhibit Topoisomerase I enzyme in DNA replication.

Adverse effects include Bone marrow suppression, Nausea and vomiting, Asthenia


EPIPODOPHYLLOTOXINSETOPOSIDETENIPOSIDE

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


ANTBIOTICS These anticancer antibiotics are extracted from Streptomyces sp.ACTINOMYCIN D – DACTINOMYCINATHRACYCLINES – DAUNORUBICIN, DOXORUBICIN, EPIRUBICIN, IDARUBICINBLEOMYCIN


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


ATHRACYCLINESDAUNORUBICINDOXORUBICINEPIRUBICINIDARUBICIN

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.


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.


HORMONAL THERAPYANTIESTROGEN THERAPYANTIANDROGEN THERAPY


ANTIESTROGEN THERAPYSELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)SELECTIVE ESTROGEN RECEPTOR DOWN REGULATOR (SERDs)AROMATASE INHIBITORS


SERMsTAMOXIFENTOREMIFENE 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


SERDsFULVESTRANT

Pure Estrogen receptor antagonist. Enhances degradation of estrogen receptors.

Adverse effects include Nausea, Headache, Hot flashes


AROMATASE INHIBITORSANASTRAZOLELETROZOLEEXEMESTANE

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.


ANTI-ANDROGENS FOR PROSTATE CANCERGnRH ANALOGSGnRH ANTAGONISTSANDROGEN RECEPTOR BLOCKERS


GNRH ANALOGSLEUPROLIDEGOSERELINTRIPTORELIN

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


GNRH ANTAGONISTSDEGARELIX

Directly inhibits GNRH activities on the Pituitary gland and prevents LH and FSH production

Adverse effects are same as GnRH analogs( Continous use)


ANDROGEN RECEPTOR BLOCKERSFLUTAMIDE NILUTAMIDEBICALUTAMIDEENZALUTAMIDE

Adverse effects are same as GNRH analogs (continuous use)


TARGETED THERAPYMONOCLONAL ANTIBODIESTYROSINE KINASE INHIBITORSMTOR INHIBITORS


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


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


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.


MTOR INHIBITORSRAPAMYCIN (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.


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