Cancer

Question 1

Alkylating Agents

Answer 1

Product strong electrophiles through that formation of carbonic or ethyleneimonium ion intermediates, which form covalent linkages by alkylation of nucleophilic moieties in DNA (N7 guanine) –> DNA damage via cross linking

Cell cycle non specific (CCNS)

Toxicity: BMS, mucosal, N&V, amenorrhea in women, male sterility, INCREASED risk of leukemia**

Resistance: Decreased permeability or uptake, increased metabolism, enhanced DNA repair, INCREASED production of glutathione (anti-oxidant)** which inactivates the alkylating agents

Question 2

Mechlorethamine

Answer 2

Nitrogen mustard

Spontaneous conversion to active

Therapeutics: Treats Hodgkin’s disease in MOPP combined therapy. Also used for treatment of cutaneous T-cell lymphoma.**

SE: N&V. BMS.

Question 3

Cyclophosphamide

Answer 3

Nitrogen mustard

Prodrug that must be converted by hepatic P450 enzymes (active form = phosphoramide mustard). Most widely used alkylating agent.

Therapeutics: ALL/CLL, non-Hodgkin’s, breast, lung and ovarian

Toxicity: N&V, BMS, HEMORRHAGIC CYSTITIC**
-Local irritation in the blader due to acrolein: Treat with hydration and administration of MESNA which inactivates acrolein

Question 4

Ifosfamide

Answer 4

Nitrogen mustard

Prodrug that must be converted by hepatic P450 enzymes

Therapeutics: Sarcoma and testicular cancer

Toxicity: Same as cyclophosphamide

Question 5

Carmustine and Lomustine

Answer 5

Nitrosoureas

Highly lipophilic and are able to cross the BBB

Therapeutics: Brain tumors

Toxicity: CNS toxicity, pulmonary fibrosis** (as well as bleomycin), N&V, BMS

Question 6

Dacarbazine

Answer 6

Triazene

Prodrug** that requires metabolic activation by the liver. Administered by IV.

Therapeutics: Hodgkin’s disease ABVD regiment. Also malignant melanoma-only officially approved but BRAF mutations have new treatment options coming**

Toxicity: N&V, BMS, Flu-like symptoms (fever, fatigue)

Question 7

Temozolomide

Answer 7

Triazene

Non-enzymatic** conversion to methyl hydrazine at physiological pH. Administered orally.

Therapeutics: Malignant gliomas***. Standard agent in combination with radiation therapy.

Toxicity: N&V, BMS, Flu-like symptoms

Question 8

Platinum Analogs

Answer 8

Do not form carbonium ion intermediates, instead they are converted to active cytotoxic forms by reacting with water to form positively charged, hydrated intermediates that react with N7 guanine (similar to alkylating agents) –> DNA damage

Question 9

Cisplatin

Answer 9

Therapeutics: Testicular, ovarian, bladder, lung and often in combination treatments

Toxicity: RENAL TOXICITY, OTOTOXICITY with hearing loss, N&V, PERIPHERAL NEUROPATHY, BMS
-Nephro, hearing and neuropathies**

Question 10

Carboplatin

Answer 10

Therapeutics: Ovarian cancer

Toxicity: BMS

Question 11

Oxaliplatin

Answer 11

Therapeutics: Gastric and colorectal

Toxicity: COLD-INDUCED ACUTE PERIPHERAL NEUROPATHY**, neutopenia

Question 12

Antimetabolites

Answer 12

Structural analogs of folic acid, purine or pyrimidine bases. Act to inhibit DNA synthesis at the S phase and are CCS.

Question 13

Methotrexate

Answer 13

Folate analog (most widely used antimetabolite)

Inhibits dihydrofolate reductase (DHFR) the enzyme that normally converts dietary folate –> tetrahydrofolate which is then required for thymidine and purine biosynthesis.

Administered intrathecally for CNS tumors (cannot penetrate the CNS)

Therapeutics: Childhood ALL and choriocarcinoma. Combo therapy for Burkitt’s lymphoma, breast, ovary, head and neck and bladder. Intrathecally for treatment of meningeal leukemia. High-dose used for osteosarcoma.

Toxicity: BM TOXICITY. GI. RENAL TOXICITY (crystalized in urine at high doses), HEPATOTOXICITY, defective oogenesis or spermatogenesis
-Treat with LEUCOVORIN (folate analog)

Mechanism of resistance

1. Reduced drug uptake
2. Increased production of DHFR (gene amplification)
3. Decreased affinity of DHFR for MTX

Question 14

Pemetrexed

Answer 14

Folate analog

Metabolized** to polyglutamate that inhibits several tetrahydrofolate-dependent enzymes involved in purine and pyrimidine synthesis, including DHFR and thymidylate synthase (TS).

Therapeutics: Colon cancer, mesothelioma, non-small cell lung cancer and pancreatic cancer

Question 15

5-Fluorouracil

Answer 15

Pyrimidine analog (S phase specific)

Pro-drug –> F-dUMP and F-dUTP.
F-dUMP: Inhibits thymidylate synthase and prevents the synthesis of thymidine (Interferes with RNA polymerase).
F-dUTP: Incorporates into RNA and interferes with RNA function.

Therapeutics: IV infusion due to toxicity to the GI. Combination therapy for breast, colorectal, gastric, head and neck, cervical and pancreatic. Topical to treat Basal Cell Carcinoma.
5-FU = breast and colorectal

Toxicity: Anorexia, vomiting, mucosal, BMS, HAND-FOOT SYNDROME (erythema, sensitivity of the palms and soles)**, cardiac toxicity

Question 16

Capecitabine

Answer 16

Prodrug converted to F-dFdU used to treat metastatic breast cancer and colorectal cancer

Question 17

Cytarabine

Answer 17

Analog of 2-deoxycytidine

Ara-C –> (deoxycytidine kinase) Ara-CMP –> Ara-CTP which competes with dCTP forcing chain termination (S-phase specific). Inhibits DNA POLYMERASE
-Inhibited by the enzyme cytadine deaminase* (resistance)

Therapeutics: AML (with an anthracycline or mitoxantrone), also ALL and blast phase CML

Toxicity: BMS, GI

Question 18

GEMcitabine

Answer 18

Analog of deoxycytidine

Active throughout the cell cycle (not S-phase specific). Effective against solid tumors.

–> (deoxycytidine kinase) dFdCMP –> dFdCDP and dFdCTP
dFdCDP: Inhibits ribonucleotide reductase**
dFdCTP: Incorporates into DNA and leads to termination

Therapeutics: First line treatment for PANCREATIC CARCINOMA**. Also non-small cell lung, ovarian, bladder, esophageal and head and neck

Toxicity: BMS, Flu-like syndrome

Question 19

6-Mercaptopurine

Answer 19

Purine Analog

Prodrug (Azathioprine) that must be metabolized by HGPRT** –> TIMP

TIMP: Inhibits first step in de novo synthesis of purine bases + blocks the formation of AMP and xanthinylic acid from inosinic acid + converted to thio-guanine ribonucleotides which are incorporated into DNA and RNA terminating synthesis

Therapeutics: Maintain remission in ALL

Drug Interaction: Allopurinol used to treat gout inhibits xanthine oxidase and thereby would elevate plasma levels of mercaptopurine**

Toxicity: BMS, hepatotoxicity** in prolonged use

Resistance: Reduced metabolic conversion of 6-MP due to decreased HGPRT, decreased drug transport

Question 20

DNA Intercalating Agents

Answer 20

Anti-tumor antibiotics
Derived from streptomyces
Bind to DNA through intercalation and block synthesis of DNA, RNA or both

Question 21

Dactinomycin (Actinomycin D)

Answer 21

First anti-tumor antibiotic

Intercalated between adjacent G-C pairs –> interferes with DNA-dependent RNA polymerase** causing inhibition of transcription + single strand DNA breaks

Therapeutics: Pediatric tumors (kids ACT out) - Wilms’, rhabdomyosarcoma and Ewing’s. Also advanced choriocarcinoma in women.

Toxicity: Severe BMS**, N&V, anorexia

Question 22

Anthracyclines

Answer 22

Type of DNA intercalating agent

Intercalate between DNA base pairs –> reduced to intermediates that donate electrons to oxygen to form superoxide –> superoxide + superoxide = hydrogen peroxide –> in the presence of Fe –> hydroxyl radical –> cleaves DNA

Question 23

Doxorubicin

Answer 23

Anthracycline

Therapeutics: BROAD - sarcomas, breast and lung carcinomas, and lymphomas

Toxicity: IRREVERSIBLE DOSE-LIMITED CARDIOTOXICITY (CARDIOMYOPATHY) + BMS, stomatitis, GI and alopecia

Resolution: Treat with DEXRAZOXANE which is an iron chelating agent to prevent free radicals***

Question 24

Daunorubicin and Idarubicin

Answer 24

Anthracycline

Therapeutics: AML (combination treatment with cytarabine/Ara-C)

Toxicity: IRREVERSIBLE DOSE-LIMITED CARDIOTOXICITY (CARDIOMYOPATHY) +BMS, stomatitis, GI and

Resolution: DEXTRAZOXANE

Question 25

Epirubicin

Answer 25

Anthracycline Therapeutics: Combo regiment (FEC) for treatment of metastatic breast and gastric Toxicity: IRREVERSIBLE DOSE-LIMITED CARDIOTOXICITY (CARDIOMYOPATHY) +BMS, stomatitis, GI and Resolution: DEXTRAZOXANE

Question 26

Bleomycin

Answer 26

Mixture of two copper peptides obtained from Streptomycin In the presence of Fe and O2** --> free radicals --> single and double strand DNA breaks. ACTS IN G2 PHASE Therapeutics: PEB combination treatment for testicular carcinomas and part of ABVD regiment for hodgkin's. Also effective agains SCC and lymphomas. Toxicity: DOSE RELATED PULMONARY TOXICITY (PULMONARY FIBROSIS)** MINIMALLY MYELOSUPPRESIVE** Cutaneous toxicity --> hyperpigmentation, hyperkeratosis, erythema

Question 27

Vinblastine

Answer 27

Vinka Alkaloid: Prevent microtubule polymerization (Work in the M phase), derived from plant vinka rosea Therapeutics: ABVD for hodgkin's and with bleomycin + cisplatin for metastatic testicular tumors Toxicity: BMS, N&V Resistance: P-glycoprotein and mutation in tubulin --> reduced binding

Question 28

Vincristine

Answer 28

Vinka Alkaloid Therapeutics: With glucocorticoids in the treatment of childhood ALL ("cristy is a young girl with ALL") and MOPP for Hodgkin's Toxicity: DOSE LIMITED NEUROTOXICITY (PERIPHERAL NEUROPATHY)** LOW TOXICITY IN BM** Resistance: P-glycoprotein and mutation in tubulin --> reduced binding

Question 29

Paclitaxel

Answer 29

Taxanes: Bind to tubulin and promote polymerization and stabalization of microtubules (chromosomes can't degrade during mitosis). Pacific yew tree. Therapeutics: Metastatic breast, ovarian, lung and head and neck Toxicity: PERIPHERAL NEUROPATHY**, neutropenia, hypersensitivity

Question 30

Docetaxel

Answer 30

Taxanes Therapeutics: Metastatic breast, ovarian, lung and head and neck + HORMONE-REFRACTORY PROSTATE CANCER** Toxicity: PERIPHERAL NEUROPATHY**, neutropenia, hypersensitivity

Question 31

Etoposide

Answer 31

Epipodophyllotoxins: Inhibit DNA topoisomerase II Therapeutics: Broad spectrum - testicular carcinoma, lung cancer and non-Hodgkin's Toxicity: BMS, mucositis **CIDE=II

Question 32

Teniposide

Answer 32

Epipodophyllotoxins Therapeutics: ALL Toxicity: BMS, mucositis **CIDE=II

Question 33

Ironotecan

Answer 33

Camptothecin Analogs: Inhibit DNA topoisomerase I Therapeutics: Advanced colorectal + lung, overain, cervical and brain Toxicity: SEVERE** BMS and diarrhea - Give loperamide to avoid diarrhea symptoms * *TECAN=I

Question 34

Topotecan

Answer 34

Camptothecin Analog Therapeutics: Ovarianand small cell lung Toxicity: SEVERE** BMS and diarrhea **TECAN=I

Question 35

Prednisone

Answer 35

Glucocorticoid: Inhibit mitosis in lymphocytes Therapeutics: ALL with vincristine, MOPP and CHOP for Hodgkin's and non-Hodgkin's, APL leukocyte activation syndrome Toxicity: Well tolerated, NO BMS

Question 36

Dexamethasone

Answer 36

Glucocorticoid Therapeutics: Used to reduce edema following radiation of brain tumors Toxicity: Well tolerated, NO BMS

Question 37

Tamoxifen

Answer 37

Selective Estrogen-Receptor Mudulator (SERM) Competed with estradiol for binding to the ER --> non functional hormone-receptor complex Therapeutics: ER+ breast cancer or prevention Toxicity: Hot flushes, hair loss, N&V, INCREASED RISK OF ENDOMETRIAL CANCER AND THROMBOEMBOLIC EVENTS**

Question 38

Fulvestrant

Answer 38

Selective Estrogen Receptor Downregulator (SERDs) Pure anti-estrogen activity --> Binds to ER with a much higher affinity than tamoxifen --> Inhibits dimerization of ER --> degradation of the receptor Therapeutics: Postmenopausal women with ER+ metastatic breast cancer

Question 39

Aminoglutethamide

Answer 39

Aromatase inhibitor Relatively weak first generation with significant toxicity

Question 40

Anastrozole and Letrozole

Answer 40

Non-steroidal Aromatase inhibitor Aromatase = First line for ER+ breast cancer

Question 41

Exemestane

Answer 41

Steroidal Aromatase inhibitor

Question 42

Leuprolide and Goserelin

Answer 42

GnRH analogs Bind to GnRH receptor and inhibit release of LH and FSH --> reduced testicular production of testosterone **Leuprolide used with Flutamide for prostate cancer (LF) Note: For complete androgen ablation therapy you need GnRH analogs and AR blockers

Question 43

Flutamide and Bicalutamide

Answer 43

Nonsteroidal androgen-receptor (AR) blockers Compete with natural hormone for binding to the androgen receptor and prevent its translocation to the nucleus **Leuprolide used with Flutamide for prostate cancer (LF)

Question 44

Hydroxyurea

Answer 44

Inhibits DNA synthesis by inhibiting the enzyme ribonucleotide reductase** Therapeutics: Myeloproliferative neoplasms (polycythemia vera and essential thrombocytopenia) + sickle cell disease

Question 45

All-trans retinoic acid (ATRA)

Answer 45

Induced differentiation in leukemic promyelocytes and produces remissions in APL (25-45 per day in two doses) Therapeutics: APL (given with anthracycline or arsenic trioxide - preferred now) Toxicity: Increased white blood cell count, fever, respiratory distress, weight gain, pleural or pericardial effusion, occasional renal failure Resistance: P450 enzymes that enhance metabolism or alterations in cytosolic retinoic acid binding protein II (CRBP II) that effect transport to its target

Question 46

Arsenic Trioxide

Answer 46

Heavy metal toxin for APL

Question 47

Thalidomide

Answer 47

Inhibits IL-6 (growth factor for myeloma cells) and inhibits angiogenesis Therapeutics: Multiple myeloma and myelodysplastic syndromes

Question 48

Interpheron alpha

Answer 48

Therapeutics: Hairy-cell leukemia, CML, and AIDs related Kapok's sarcoma

Question 49

Verapamil

Answer 49

Used to inhibit drug transporters such as P-glycoprotein which uses ATP (it's a calcium channel antagonist)

Question 50

Imatinib

Answer 50

Tyrosine kinase inhibitor: Kinase catalyzes the transfer of a phosphate group from ATP to it's substrate (protein, lipid or carb) Selective agonist of Abl tyrosine kinase. Binds to the same site that ATP binds blocking the Bcr-Abl genes ability to phosphorylate and activate the proteins involved in malignant formation Pharmacokinetics: Orally (400 mg/day), Half life = 13-16 hours (oral 1/day). Metabolized by cytochrome P450 (3A4) enzyme Therapeutics: CML** (first line therapy), but also GIST, ALL, CEL, dermatofibrosarcoma protuberant, systemic mastocytosis Toxicity: N&V, fluid retention, muscle cramps, arthralgia and some BMS Resistance: Reactivation of Bcr-Abl kinase due to mutations, amplification or molecular abnomalities

Question 51

Nilotinib

Answer 51

Structurally similar to imatinib (oral 2/day) Therapeutics: CML** first line therapy after imatinib. Better fit in Bcr-Abl > affinity than imatinib and active against mutants (imatinib resistant cases) Toxicity: Myelosuppression, QT prolongation, sudden death, hepatotoxicity, elevated serum lipase, electrolyte abnormalities Contraindication: Hypokalemia, hypomagnesia, long QT syndrome

Question 52

Dasatinib

Answer 52

Different structure than imatinib (oral 1/day) Therapeutics: CML** first line therapy after imatinib. ATP mimetic and binds ABL kinase pocket. Greater affinity (300 times). Active against imatinib resistant strains. Toxicity: Myelosuppression, bleeding, fluid retention, cardiac problems, pulmonary arterial hypertension**, etc

Question 53

Bosutinib

Answer 53

Second line therapy for CML Ineffective against T315I mutation Toxicity: GI

Question 54

Ponatinib

Answer 54

Second line therapy for CML Effective against T315I mutation Toxicity: Vascular occlusion, heart failure, hepatotoxicity

Question 55

Trastuzumab (Herceptin)

Answer 55

Humanized monoclonal antibody against ErbB2/Her2-neu Interferes with ErbB2 signals (interacts with all others as well) --> degradation of the receptor Loading dose: 4mg/kg. Maintanence: 2mg/kg. Want desired trough serum concentration of 10-20micrograms/ml. Half life = 8.3 +/- 5 days Therapeutics: ErbB2 + Breast cancer. Used in combination with taxanes (paclitaxel or docetaxel)** --> Trastuzumab might enhance apoptotic effects of other drugs. Also gastric/gastro-esophageal cancer Toxicity: Hypersensitivity (even with humanized version)**, ventricular dysfunction and CHF, and can enhance cardiac toxicity of doxorubicin**

Question 56

Ado-trasuzumab emtansinde (T-DM1)

Answer 56

Trastuzumab is conjugated to DM1 which is a derivative of Maytansine (microtubule inhibitor) Provides selective delivery to ErbB2 + cancer cells and the actions are still in tact Toxicity: Ventricular dysfunction**, interstitial lung disease, infusion associated reactions, hepatotoxicity**, embryo-fetal toxicity and birth defects

Question 57

Cetuximab

Answer 57

Anti-ErbB1 monoclonal antibody Binds to ErbB1 with similar affinity as EGF or TGF-alpha Therapeutics: EGFR expressing metastatic colorectal cancer (with ironotecan, 5-FU or leucovorin) with wild type K-ras. Predicted to work better in combination with cisplatin Toxicity: Allergic reaction ,cardiac sudden death, dermatologic problems**, renal failure, pulmonary embolism, hypomagnesemia, hypocalcemia

Question 58

Rituximab

Answer 58

Chimeric monoclonal antibody with variable region of mice IgG but constant region and Fc portion from humans Binds CD20 on all B cells --> eliminates response --> induces apoptosis, complement response and cell mediated cytotoxicity Therapeutics: Non Hodgkins follicular lymphoms (differentiated B-cell lymphoma), rheumatoid arthritis Toxicity**: Fatal infusion reactions, severe mucocutaneous reactions, hepatitis b virus reactivation, PML, tumor lysis syndrome, infections, cardiovascular, renal, bowel obstruction

Question 59

Vemurafenib

Answer 59

Inhibits BRAF serine threonine kinase in this specific melanoma BRAF --> MEK --> ERK --> action Therapeutics: Unrescectable stage III or IV melanoma with BRAF mutation Toxicity: Cutaneous SCC**, can cause QT prolongation** (ventricular arrhythmias) Contraindications: Should not be given to melanomas harboring wild type BRAF*, long QT syndrome

Question 60

Debrafenib

Answer 60

Inhibits BRAF Therapeutics: Unrescectable stage III or IV melanoma with BRAF mutation Toxicity: Seriously febrile drug reactions**, uveitis, iritis, may cause male infertility Contraindication: Should not be given to melanomas harboring wild type BRAF

Question 61

Trametinib

Answer 61

Inhibits MEK Therapeutics: Unrescectable stage III or IV melanoma Toxicity: Serious skin toxicity**, cardiomyopathy, retinal, lung, female infertility Contraindication: Should not be given to melanomas harboring wild type BRAF or patients previously treated with BRAF inhibitors

Question 62

Erlotinib

Answer 62

Inhibits EGFR tyrosine kinase (Exon 19 deletion or exon 21 substitution). Metabolized by CYP3A4. Could induce increased bleeding (contraindicated when on warfarin) Oral 1/day Therapeutics: Non-small cell lung carcinoma (NSCLC) Toxicity: Rash, diarrhea, loss of appetite, weight loss, N&V, mouth sores, liver or renal failure, interstitial lunch disease, increased bleeding,

Question 63

Gefitinib

Answer 63

Inhibits EGFR tyrosine kinase and used for NSCLC (Exon 19 deletion or exon 21 substitution) Oral 1/day Toxicity: Interstitial lung disease, liver damage, GI perforation

Question 64

Afatinib

Answer 64

Inhibits EGFR tyrosine kinase and used for NSCLC (Exon 19 deletion or exon 21 substitution) Oral 1/day Toxicity: Dyspnea, fatigue, pulmonary toxicity/ILD, sepsis, pneumonia

Question 65

Lapatinib

Answer 65

Inhibits EGFR and ErbB2 Therapeutics: Advanced or metastatic breast cancer with HER2 overexpression (combination with letrozole for postmenopausal women) Toxicity: Liver damage (fatal), QT prolongation (capectiabine lowers effects)

Question 66

Nivolumab

Answer 66

Inhibits PD-1 (programmed cell death protein 1) which interferes with immune systems attack on melanoma cells. As well as SCC of the lung** SE: Severe immune mediated side effects involving healthy organs including lung, colon, liver, kidneys and hormone producing glands