Chemotherapy

Question 1

Define primary chemotherapy?

Answer 1

Chemotherapy indicated when neoplasms are disseminated and not amenable to surgery

Question 2

Define adjuvant chemotherapy?

Answer 2

Chemotherapy used to attack micrometastases following surgery and radiation

Question 3

Define neoadjuvant chemotherapy?

Answer 3

Chemotherapy given prior to surgery to shrink the cancer

Question 4

Methotrexate

Answer 4

MOA: inhibits dihydrofolate reductase > decrease synthesis of dTMP and purine nucleotides > decrease DNA, RNA, protein synthesis > cell death

AE: common is stomatits, myelosuppression, alopecia, nausea, and vomiting. Others are renal damage, hepatic fibrosis/cirrhosis, pneumonitis, and neurological toxicites

HL: metabolized by folylpolyglutamate synthase (FPGS) to polygulamates (MTX-PGs). Given in combination with Leucovorin which is N⁵-formyl-THF which provides normal tissue with reduced folate

Question 5

What are the two purine analogs?

Answer 5

6-mercaptopurine and 6-thioguanine

Question 6

6-mercaptopurine

Answer 6

MOA: convereted to thio-IMP by HGPRT > inhibits first step of de novo purine ring biosynthesis and blocks formation of AMP/GMP from IMP > dysfunctional RNA and DNA > cell death

AE: nausea, vomiting, diarrhea, bone marrow supression, and hepatotoxicity

HL: metabolized by xanathine oxidase to thiouric acid and by thiopuring methyltransferase (TPMT). If allopurinol is given with reduce hyperuricemia dose of 6-MP must be reduced because allopurinol is xanthine oxidase inhibitor.

Question 7

6-thioguanine

Answer 7

MOA: converted to nucleotide > inhibits purine synthesis and the phosphorylation of GMP to GDP

AE: nausea, vomiting, diarrhea, bone marrow suppression, hepatotoxicity

HL: allopurinol does not potentiate 6-TG action because very little is metabolized to thiouric acid. Metabolized by thiopuring methyltransferase (TPMT)

Question 8

What are the 3 pyrimidine analogs?

Answer 8

5-fluorouracil, Capecitabine, and Cytarabine

Question 9

5-fluorouracil

Answer 9

MOA: converted to 5-FdUMP and 5-FUTP > inhibits thymidylate synthase > thymineless death

AE: nause vomiting, alopecia, bone marrow depression and hand-foot syndrome

HL: combined with leucovorin for colorectal cancer because increasing levels of N⁵,N¹⁰-methylene-THF potentiates activity

Question 10

Capecitabine

Answer 10

MOA: same as 5-FU

AE: same as 5-FU

HL:

Question 11

Cytarabine (ARA-C)

Answer 11

MOA: analog of deoxycytidine > phosphorylated to triphosphate > incorporated into DNA > inhibits DNA polymerase

AE:

HL:

Question 12

Anthracyclines (Doxorubicin and Daunorubicin)

Answer 12

MOA: inhibition of topoisomerase II, intercalation in DNA with consequent blockade of DNA/RNA synthesis and strand breakage, binding to cell membranes to alter fluidity/ion transport, generation of free radicals

AE: myelosuppression, cardiotoxicity

HL: dexrazoxane can redue the cardiotoxicity

Question 13

Bleomycin

Answer 13

MOA: mixture of glycopeptides > DNA-bleomycin-Fe²⁺ > oxidation to bleomycin-Fe³⁺ > reacts with O₂ forming free radicals > strand breakdown

AE: very little myelosuppression, pulmonary toxicity (pneumonitis, fibrosis)

HL: cell-cycle specific with arrest cells in G2 phase

Question 14

What are the different types of alkylating agents?

Answer 14

Nitrogen mustards, nitrosoureas, other alkylating agents, and platinum coordination complexes

Question 15

What are the 3 nitrogen mustards?

Answer 15

Mechlorethamine, cyclophasphamide, and melphalan

Question 16

Mechlorethamine

Answer 16

MOA: alkyating > cell death

AE: severe nausea/vomiting, severe bone marrow depression, alopecia, immunosuppression,

HL: powerful vesicant so only given by IV

Question 17

Cyclophosphamide

Answer 17

MOA: alkylating > cell death

AE: nasuea/vomiting, bone marrow depression, hemorrhagic cystitis, alopecia, and sterility

HL: its a prodrug, most widely used, and mesna + fluid intake is taken to prevent acrolein buildup leading to hemorrhagic cystitis

Question 18

Melphalan

Answer 18

MOA: alkylating agent > cell death

AE: bone marrow suppression

Question 19

What are the 2 nitrosoureas?

Answer 19

Carmustine and lomustine

Question 20

Nitrosoureas

Answer 20

MOA: alkylation > cell death

HL: very lipophilic, cross BBB, treatment of brain tumors

Question 21

What the the 3 other alkylating agents?

Answer 21

Busulfan, dacarbazine, and procarbazine

Question 22

Busulfan

Answer 22

MOA: alkylating

AE: myelosuppression and pulmonary fibrosis

Question 23

Dacarbazine

Answer 23

MOA: methylating agent after activation in liver

AE: nausea/vomiting, myelosuppression mild to moderate

HL: given IV

Question 24

Procarbazine

Answer 24

MOA: converted by liver P450 to alkylating metabolites

AE: bone marrow depression, nausea/vomiting, weak MAO inhibitor, disulfiram-like reaction, mutagenic/teratogenic

Question 25

What are the 2 platinum coordintation complexes?

Answer 25

Crisplatin and carboplatin

Question 26

Crisplatin

Answer 26

**MOA:** inhibit DNA synthesis and bind DNA through cross-links **AE:** myelosuppression mild to moderate, nausea/vomiting, ototoxicity, peripheral neuropathy, _nephrotoxicity_ **HL:** _Amifostine_ reduced the renal toxicity

Question 27

Carboplatin

Answer 27

**MOA:** inhibit DNA synthesis and bind DNA through cross-links **AE:** less nausea, neurotoxicity, ototoxicity, and _nephrotoxicity_ than cisplatin but dose limiting toxicity is myelosuppression

Question 28

What are the 2 type of microtubule inhibitors and what 2 drugs belong to each group?

Answer 28

Vinca alkaloids: vincristine and vinblastine Taxanes: paclitaxel and docetaxel

Question 29

Vinca Alkaloids

Answer 29

**MOA:** bind beta-tubulin \> inhibit ability to polymerize into microtubules \> apoptosis **AE:** vincristine is _peripheral neuropath_, bone marrow suppression mild, and alopecia. Vinblastine is _myelosuppression_ as dose limiting **HL:** mitotic arrest in metaphase

Question 30

Taxanes

Answer 30

**MOA:** bind beta-tubulin subunit of microtubules \> promote microtubule polymerization **AE:** paclitaxel is _hypersensitivity_, myelosuppression, _peripheral neuropathy_, alopecia. Docetaxel is myelosupression, _peripheral neuropathy_, fluid retention, alopecia, and mucositis. **HL:** hypersensitivity reduced by dexamethaone, diphenhydramine, and an H₂ blocker. Also for docetaxel dexamethasone is required to prevent fluid retention.

Question 31

Etoposide

Answer 31

**MOA:** inhibits topoisomerase II \> DNA damage by strand breakage

Question 32

Camptothecins (topotecan and irinotecan)

Answer 32

**MOA:** inhibit topoisomerase I \> DNA damage

Question 33

What are the 3 types of hormonal agents?

Answer 33

Glucocorticoids, estrogen inhibitors, androgen inhibitors

Question 34

Prednisone

Answer 34

**MOA:** glucocorticoids are lympholytic and supress mitosis in lymphocytes **HL:** used for _acute leukemia and malignant lymphomas_

Question 35

What are the 3 types of estrogen inhibitors?

Answer 35

Selective Estrogen-Receptor Modulators (SERMs), Selective Estrogen-Receptor Downregulators (SERDs), and Aromatase Inhibitors (AIs)

Question 36

Tamoxifen

Answer 36

**MOA:** bind estrogen receptors and act as agonist or antagonist depending on tissue **HL:** antagonist on receptor-positive breast cancer

Question 37

Raloxifene

Answer 37

**MOA:** antiestrogen in the uterus and breast while promoting estrogenic effects in bone to inhibit resorption. **HL:** prevention of postmenopausal osteoporsis and prophylaxis of breast cancer

Question 38

Fulvestrant

Answer 38

**MOA:** binds estrogen receptor \> inhibits dimerization \> increases its degredation **HL:** estrogen receptor mediated transcription is abolished

Question 39

Anastrozole & Letrozole

Answer 39

**MOA:** nonsteroidal reversible competitive inhibitor of aromatase

Question 40

Exemestane

Answer 40

**MOA:** steroidal and irreversible inhibitor of aromatase

Question 41

What are the two groups of androgen inhibitors?

Answer 41

Gonadotropin-releasing hormone agonists and androgen receptor blockers

Question 42

Goserelin and Leuprolide

Answer 42

**MOA:** GnRh agonist \> initial surge of LH/FSH levels \> inhibition of gonadotropin release \> testosterone drop to 10% in a month **HL:** initial surge can be conteracted by concurrent administration of _flutamide_ for 2-4 weeks

Question 43

Flutamide

Answer 43

**MOA:** metabolized to active metabolite that acts as competitive antagonist of androgen receptor prevent translocation to nucleus **HL:** synthetic nonsteroidal antiandrogen

Question 44

What are the 5 inhibtors of receptor tyrosine kinases and what does each do?

Answer 44

**Lapatinib**: inhibitor of EGFR and ErbB2 tyrosine kinase **Erlotinib:** inhibitor of EGFR tyrosine kinase **Gefitinib**: inhibitor of EGFR tyrosine kinase **Imatinib:** inhibitor of the tyrosine kinase of Bcr-Abl **Trastuzumab:** monoclonal antibody against ErbB2

Question 45

Asparaginase

Answer 45

**MOA:** hydrolyzing sereum asparagine \> depriving cell of asparagine necessary for protien synthesis \> cell death **AE:** hypersensitivity, decrease clotting factors, liver abnormalities, ammonia toxicity (pancreatitis, seizures, coma)

Question 46

Hydroxyurea

Answer 46

**MOA:** inhibits ribonucleotide reductase \> depletion of deoxynucleoside triphosphate pools \> inhibited DNA synthesis \> kills cells in S phase

Question 47

Interferon alpha

Answer 47

approved for hair cell leukemia, chronic myelogenous leukemia (CML), malignant melanoma, and Kaposi's sarcoma