ANTI-CANCERS

Question 1

INDICATIONS FOR CHEMOTHERAPY:

Answer 1

Chemotherapy is presently used in four main clinical settings:

1. Primary (induction) chemotherapy .
2. Neoadjuvant chemotherapy .
3. Adjuvant chemotherapy .
4. Site-directed chemotherapy.

Question 2

PRIMARY CHEMOTHERAPY

Answer 2

• Chemotherapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists.
• The goals of therapy are to:

1. Relieve tumor related symptoms.
2. Improve overall quality of life.
3. Prolong time to tumor progression.

Question 3

NEOADJUVANT CHEMOTHERAPY

Answer 3

• Chemotherapy is administered before surgery.
• The goal is to reduce the size of the primary tumor so that surgical resection can then be made easier.

Question 4

ADJUVANT CHEMOTHERAPY

Answer 4

Administration of chemotherapy after local treatment modalities (e.g. surgery) has been performed.

Destroys microscopic cells that may be present after local treatment modalities has been done.

• Reduces the incidence of both local and systemic recurrence and to improve the overall survival of patients.

Question 5

SITE-DIRECTED CHEMOTHERAPY

Answer 5

• Direct instillation into sanctuary sites (intrathecal or peritoneal).
• Regional perfusion of the tumor(e.g. Intra- arterial)

Question 6

TUMOR SUSCEPTIBILITY TO CHEMOTHERAPY

GROWTH FRACTION?

Answer 6

• GROWTH FRACTION = the percentage of actively dividing cells at any given point in time.
• Malignant neoplasms with high growth fraction (E.g. leukemia and lymphoma) are more sensitive to chemotherapeutic drugs.
• Low growth fraction tumors (Solid tumor e.g. carcinomas of the colon, lung cancer) are less responsive to chemotherapeutic drugs.

Question 7

TREATMENT PROTOCOLS FOR CHEMOTHERAPY

Answer 7

• Combination chemotherapy is the standard approach in the management of many tumors because it:

1. Provides maximal cell kill within the range of toxicity tolerated by the host for each drug.
2. Drug combinations are effective against a broader range of cell lines.
3. Some combinations of anticancer drugs appear to exert

synergistic effect.

4. May prevent or slow the subsequent development of cellular drug resistance.

Question 8

LOG KILL HYPOTHESIS

Answer 8

• The log kill hypothesis proposes that the action of cytotoxic drugs follows first order kinetics.
• A given dose of chemotherapy kills a CONSTANT FRACTION of a tumor cell population (rather than a constant number of cells).
• Repeated doses of chemotherapy -with appropriate frequency- are required to eradicate the tumor cells.

Question 9

CHEMOTHERAPY CHALLENGES:

Answer 9

1. Toxicity of chemotherapy to normal cells.

• Most traditional chemotherapeutic agents currently in use appear to exert their effect on cell proliferation.
• Proliferation is a characteristic of many normal cells as well as cancer cells, most chemotherapeutic agents have toxic effects on normal cells, particularly those with rapid rate of turnover, such as bone marrow and mucous membrane cells.

2. Resistance of tumor cells to chemotherapy.

Question 10

CHEMOTHERAPY TOXICITY:

COMMON ADVERSE EFFECTS

Answer 10

1) NAUSEA/VOMITING

–> can be treated with 5HT3 blockers and NK1 inhibitors

2) STOMATITIS –> inflammation of the mucous membranes of the mouth

3) ALOPECIA –> HAIR LOSS

4) MYELOSUPPRESSION

FILGRASTIM is used to treat neutropenia

Question 11

RESISTANCE TO CYTOTOXIC DRUGS

Answer 11

PRIMARY RESISTANCE
• No response to the drug on the first exposure.

ACQUIRED RESISTANCE
• Single drug resistance

• Due to increased expression of one or more genes.
• Multidrug resistance (MDR)
• Resistance emerges to several different drugs after _exposure to a single agent.***_

P-glycoprotein (permeability glycoprotein) is the most important efflux pump responsible for multidrug resistance. Hence the other name for this pump is multidrug resistance protein 1 (MDR1)

Question 12

CLASSIFICATION OF ANTI-CANCER DRUGS

Answer 12

• Cell cycle-specific drugs:
Antineoplastic drugs that exert their action only on cells traversing the cell cycle.

Cell cycle-nonspecific drugs:

Can kill tumor cells whether they are cycling or resting in the G0 compartment. (Although cycling cells are more sensitive).

• In general cell cycle-specific drugs are most effective in hematologic malignancies and other tumors in which a large proportion of the cells are proliferating or are in the growth fraction.
• Cell cycle-nonspecific drugs are useful in low- growth fraction solid tumors as well as in high- growth-fraction tumors.

Question 13

CELL CYCLE SPECIFIC AGENTS:

Answer 13

1) ANTIMETABOLITES
2) BLEOMYCIN
3) MICROTUBULE INHIBITORS
4) EPIPODOPHYLLOTOXINS
5) CAMPTOTHECINS

Question 14

CELL CYCLE NON-SPECIFIC AGENTS

Answer 14

1) ALKYLATING AGNETS
2) PLATINUM COORDINATION COMPLEXES
3) ANTITUMOR ANTIBIOTICS

Question 15

ANTIMETABOLITES (cell cycle specific agent)

Answer 15

1) FOLATE ANALOGS
2) PURINE ANALOGS
3) PYRIMIDINE ANALOGS

Question 16

METHOTREXATE (MTX)

Answer 16

ANTI-CANCER ANTIMETABOLITE FOLATE ANTAGONIST

MTX undergoes Intracellular conversion to MTX polyglutamates which bind and inhibit dihydrofolate reductase(DHFR) enzyme.

This results in inhibition of the synthesis of tetrahydrofolate(THF) which is involved in denovo synthesis of:

1. deoxythymidylate nuclotides → Inhibition DNA synthesis.
2. Purine nucleotides → Inhibition DNA and RNA synthesis.

Question 17

METHOTREXATE CLINICAL APPLICATIONS

AE:

Answer 17

• Breast cancer, head and neck cancer, osteogenic sarcoma, bladder cancer, choriocarcinoma, primary central nervous system lymphoma and non-Hodgkin’s lymphoma.

AE:

• Stomatitis
• Mucositis
• Nausea, vomiting and diarrhea.

• Myelosuppression.

• *• Pulmonary fibrosis.**
• *• Hepatotoxicity.**

Question 18

LEUCOVORIN

Answer 18

-is folinic acid, is givin WITH methotrexate to avoid adverse effects

–> it provides cells with reduced folate to minimize side effects

Question 19

6-MERCAPTOPURINE

MOA:

Answer 19

PURINE ANTAGONIST (ANTIMETABOLITE)

-has a very similar structure to HYPOXANTHINE

Mechanism of action:

Thiol analog of hypoxanthine.

 Converted to the nucleotide 6-MP ribose phosphate (6-MPRP, also known as thio-inosinic acid or TIMP) by the salvage pathway enzyme, HGPRT.

 TIMP inhibits phosphoribosyl pyrophosphate AMIDOTRANSFERASE enzyme which catalyzes the rate limiting step of the de novo purine ring biosynthesis.

 Thio-IMP also blocks formation of AMP and GMP from IMP.

 The monophosphate form is metabolized to the triphosphate form, which can then be incorporated into both RNA and DNA. This leads to dysfunctional DNA and RNA.

Question 20

6-MERCAPTOPURINE

CLINICAL APPLICATIONS

ADVERSE EFFECTS?

Answer 20

Clinical applications:

6-MERCAPTOPURINE –> 6 y/o’s get it to help cap off their CHILDHOOD ALL

• _***Childhood acute leukemia (ALL).***_

Adverse effects:

• Nausea, vomiting and diarrhoea.
• Hepatotoxicity.

• Bone marrow suppression.

Question 21

6-MERCAPTOPURINE

inactivated by what? Why is this a problem?

Answer 21

1. 6-MP is inactivated by xanthine oxidase. This is an important issue because the Purine analog Allopurinol, a potent xanthine oxidase inhibitor, is used in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis.
   - Because Allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of 6-mercaptopurine must be reduced.

2. The 6-MP is also metabolized by the enzyme thiopurine methyltransferase (TPMT).

–> Patients who have partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities this why the dose of 6-MP should be reduced.

Question 22

6-THIOGUANINE

Answer 22

PURINE ANTAGONIST (ANTIMETABOLITE)

-converted to the nucleotide TGMP by HGPRT

–> TGMP then

1. Inhibits the synthesis of the Purine nucleotides (by inhibiting PRPP amidotransferase).
2. Inhibit the phosphorylation of GMP to GDP by Guanylate kinase enzyme
3. Can be converted to TGTP and dTGTP which incorporate into RNA and DNA respectively.

Question 23

6-THIOGUANINE

CLINICAL APPLICATIONS

Answer 23

6-THIOGUANINE –> 6-T –> ONLY has interactions with the TPMT (has no A in it so has NO interaction with ALLOPURINOL)

-Clinical applications:
• Nonlymphocytic leukemias.

• Adverse effects:
  • Nausea, vomiting and diarrhoea. • Hepatotoxicity.
  • Bone marrow suppression.

NOTE: HAS NO INTERACTION WITH ALLOPURINOL

but DOES get metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring.

–> Patients who have partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities this why the dose of 6-TG should be reduced.

Question 24

PYRIMIDINE ANALOGUES

Answer 24

can only make pyramids out of 5 blocks, not out of 6 or any even number….. therefore 5-FLUOROURACIL (the 6’s are for purines)

will be A BIND to make a pyramid

1) 5-FLUOROURICIL
2) CAPECITABINE
3) GEMCITABINE
4) CYTARABINE

Question 25

5- FLUOROURACIL MOA

Answer 25

PYRIMIDINE ANALOG ## Footnote * Is administered **_intravenously._** * Given topically for skin cancer. * Is mainly catabolized by the enzyme \*\*\*_**Dihydropyrimidine dehydrogenase (DPD).\*\*\*\***_ * A partial or complete deficiency of the DPD enzyme results in severe toxicity. MOA: 1. **_inhibits THYMIDYLATE SYNTHASE_** --\> decreases DNA synthesis 2. also gets incorporated into RNA

Question 26

5-FLUOROURACIL clinical applications AE

Answer 26

AE: 5-FLUOROURACIL --\> hands and feet each and 5 fingers or toes therefore it gives you HAND-FOOT SYNDROME COLON also has only 5 letters in it • First line drug against **_COLORECTAL CANCER_** It also has activity against a wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus. **_Given topically for skin cancer._** **_AE:_** Myelosuppression. Gastrointestinal toxicity in the form of mucositis and diarrhea. Neurotoxicity. Skin toxicity manifested by the **_hand-foot syndrome._**

Question 27

CAPECITABINE

Answer 27

PYRIMIDINE ANTAGONIST ## Footnote CAPE --\> 4 limbs + CAPE --\> therefore is a 5-FU prodrug. Is a superhero --\> goes right to the tumor to get catalyzed for the last step Orally available **_prodrug of 5-FU_** Activated by a three-steps enzymatic conversion to 5-FU. The **_first two_** steps occur in the **_liver ._** The **last step** occurs in the **_tumor_** and it is catalyzed by the enzyme \*\*\*_**Thymidine phosphorylase.\*\*\***_ The expression of thymidine phosphorylase is **_higher in many solid tumors_** than in corresponding normal tissue, particularly in **_breast cancer and colorectal cancer._**

Question 28

CAPECITABINE CLINICAL APPLICATIONS ADVERSE EFFECTS

Answer 28

EXACT SAME AS 5-FU BUT LESS SIDE EFFECTS • First-line treatment of **_metastatic colorectal cancer._** **_• Metastatic breast cancer. (superhero gets all the chicks)_** AE: • Diarrhea Hand-foot syndrome. Myelosuppression, nausea, vomiting, and mucositis are also observed with this agent, however their **_incidence is significantly less_** than that observed with intravenous 5-FU.

Question 29

DEOXYCYTIDINE ANALOGS

Answer 29

1) CYTARABINE 2) GEMCITABINE

Question 30

CYTARABINE MOA

Answer 30

ABC --\> **_C_**ytara**_bine_** BINDS/inhibits to the SITE (cyte) of DNA **_alpha_** and **_beta_** • Converted to **_Cytarabine triphosphate_** which then: 1. Competitively **_inhibits DNA polymerase-α_** (blockade of DNA synthesis). 2. Competitively **_inhibits DNA polymerase-β_** (blockade of DNA repair). 3. **_Incorporated into RNA and DNA_**. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA.

Question 31

CYTARABINE CLINICAL APPLICATIONS AE

Answer 31

• Its activity is *limited exclusively to* **_hematologic malignancies_**, including * acute myelogenous leukemia and * non-Hodgkin’s lymphoma. **_• Not active against solid tumors._** **_AE:_** Myelosuppression Mucositis Nausea Vomiting Neurotoxicity (when high-dose therapy is administered).

Question 32

GEMCITABINE MOA

Answer 32

MOA: GEM that BINDS to and INHIBITS DNA in the TRIphosphate form • Phosphorylated to nucleoside di- and triphosphate, which inhibit DNA synthesis. This Inhibition is a result of: * 1) Inhibition of ribonucleotide reductase by Gemcitabine diphosphate, which **_reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA._** * 2) Incorporation of Gemcitabine triphosphate i**_nto DNA which results in chain termination._**

Question 33

GEMCITABINE clinical applicaitons AE

Answer 33

**_• Broad-spectrum activity against:_** 1. Solid tumors: including **_Pancreatic cancer,_** non small cell lung carcinoma, bladder cancer, ovarian cancer, soft tissue and sarcomas. 2. Hematologic malignancies :( non-Hodgkin’s lymphoma). :( non-Hodgkin’s lymphoma). AE: **_Renal microangiopathy syndromes, including_** **_1) hemolytic-uremic syndrome and_** **_2) thrombotic thrombocytopenic purpura (rarely)._** -can also have ELEVATED LIVER ENZYEMS (AST/ALT)

Question 34

MICROTUBULE INHIBITORS

Answer 34

 Microtubules are essential for formation of mitotic spindle. --\> required during MITOSIS  This class includes: **_Vincaalkaloids:_** A. Vinblastine. B. Vincristine. **_Taxanes:_** A. Paclitaxel. B. Docetaxel.

Question 35

VINCA-ALKALOIDS PK + MOA:

Answer 35

PK: * Metabolized by the liver P450 system. * Excreted in feces. * **_Dose modification_** is required in the setting of liver dysfunction. MOA: * Vinca alkaloids bind to **_β-tubulin._** This disrupts assembly of microtubules. * This inhibitory effect results in **_mitotic arrest in metaphase_**. * Microtubules are essential to many cellular functions such as movement, phagocytosis and axonal transport. AE: of the Vinca alkaloids such as neurotoxicity may be due to disruption of these functions.

Question 36

VINBLASTINE

Answer 36

VINCA-ALKALOID ## Footnote Clinical applications: • Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer and **_germ cell cancer._** Adverse effects: • Nausea and vomiting. **_• Bone marrow suppression._** • Alopecia. \*Potent vesicant, and care must be taken in its administration.

Question 37

VINCRISTINE

Answer 37

VINCA ALKALOID ## Footnote Clinical applications: **_1. Hematological malignancies:_** • Acute lymphoblastic leukemia, Hodgkin’s and non- Hodgkin’s lymphoma. _**\*\*\*2. Pediatric tumors:\*\*\***_ • Rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor. **_ADVERSE EFFECTS:_** Myelosuppression. Alopecia. Syndrome of inappropriate ADH secretion (SIADH). _**Neurotoxicity with peripheral neuropathy.\*\*\*\***_ Paralytic ileus. Optic atrophy.

Question 38

TAXANES

Answer 38

MICROTUBULE INHIBITOR ## Footnote Pharmacokinetics: * Metabolized extensively by the liver P450 system and nearly 80% of these drugs is excreted in feces via the h**_epatobiliary route._** * **_Dose reduction_** is required in patients with liver dysfunction. MOA: * Taxanes bind to the **_β-tubulin subunit_** of microtubules at a site **_distinct from the Vinca alkaloid binding site._** * Unlike the Vinca alkaloids, _**Taxanes \*\*\*promote microtubule polymerization and inhibit depolymerization.\*\*\*\***_ * Stabilization of the microtubules in a polymerized state arrests cells in mitosis and eventually leads to the activation of apoptosis.

Question 39

PACLITAXEL

Answer 39

MICROTUBULE INHIBITOR: TAXANE ## Footnote Clinical applications: • **_Solid tumors_** including: ovarian advanced breast, lung cancer, head and neck, esophageal, prostate, and bladder cancers and AIDS-related Kaposi’s sarcoma. Nausea and vomiting. Hypotension. Arrhythmias. Neurotoxicity. Hypersensitivity reactions. **_ABRAXANE_** -albumin-bound Paclitaxel formulation- is approved for use in **_metastatic breast cancer_**. (Better side effect profile).

Question 40

albumin-bound Paclitaxel formulation- is approved for use in metastatic breast cancer. (Better side effect profile).

Answer 40

ABRAXANE

Question 41

DOCETAXEL

Answer 41

**_MICROTUBULE INHIBITOR: TAXANE_** ## Footnote Clinical applications : * Second- line therapy in **_advanced breast cancer and non-small cell lung cancer._** * Major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum- refractory ovarian cancer, and bladder cancer. AE: * Hypersensitivity. * \*\*\*\***_Profound_** myelosuppression.\*\*\*\* KNOW THIS * Fluid retention:Pre-treatment with \*\*\*_**Dexamethasone\*\*\***_ is required to prevent fluid retention. * \*\*\*\*Neurotoxicity: _**does not cause neuropathy as frequently as Paclitaxel.\*\*\*\*\*\*\*\*\***_

Question 42

1. Etoposide 2. Teniposide

Answer 42

belong to the EPIPODOPHYLLOTOXINS This class includes: 1. Etoposide 2. Teniposide MOA: * **_Inhibit topoisomerase II_**, resulting in DNA damage through strand breakage. (prevents re-ligaiton of strand breaks) * Block cells in the **_late S-G2 phase._**

Question 43

ETOPOSIDE + TENIPOSIDE clinical applications + AE

Answer 43

EPIPODOPHYLLOTOXINS ## Footnote **_Clinical Applications:_** **_A) Etoposide_** is indicated for 1) **_testicular cancer_** and 2) **_small cell lung cancer._** **_B) Teniposide_** is indicated for 1) **_refractory childhood ALL_** **_Adverse effects:_** • Nausea and vomiting. * Alopecia. * Myelosuppression.

Question 44

TOPOTECAN

Answer 44

CAMPTOTHECIN ## Footnote MOA: They inhibit the activity of **_topoisomerase I_**, the key enzyme responsible for *cutting and religating single DNA strands*. Inhibition of this enzyme results in DNA damage. Clinical applications: * Second-line therapy for advanced **_ovarian cancer_** following initial treatment with platinum-based chemotherapy. * Second-line therapy of **_small cell lung cancer._** **_PK:_** • The main route of elimination is **_renal excretion_** and dosage must be adjusted in patients with renal impairment. **_Adverse effects:_** * Nausea and vomiting. * Myelosuppression.

Question 45

IRINOTECAN

Answer 45

CAMPTOTHECIN ## Footnote * Pharmacokinetics: * Irinotecan is a **_prodrug_** converted in the liver to an active metabolite. • Irinotecan and its metabolites are **_mainly eliminated in bile and feces_**, and dose reduction is required in case of liver dysfunction. Clinical applications: • **_Metastatic colorectal cancer_** (combined with 5- FU and Leucovorin). Adverse effects: * Myelosuppression. * Diarrhea.

Question 46

ANTITUMOR ANTIBIOTICS

Answer 46

This class includes: * *_1. Bleomycin = cell cycle specific_** * *_2. Anthracyclines = cell cycle NON-SPECIFIC_** - Doxorubicin - Daunorubicin

Question 47

BLEOMYCIN

Answer 47

ANTITUMOR ANTIBIOTIC: CELL CYCLE SPECIFIC ## Footnote -is a cell cycle specific agent **_acting at G2_** * Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. * It acts by **_binding to DNA_**, which results in **_single- and double-strand breaks following free radical formation._**

Question 48

BLEOMYCIN PK CLINICAL APPLICATIONS

Answer 48

ANTITUMOR ANTIBIOTIC: CELL CYCLE SPECIFIC (G2) ## Footnote Pharmacokinetics: * It can be administered subcutaneously, intramuscularly, or intravenously. * Elimination of Bleomycin is mainly via renal excretion, and **_dose modification_** is recommended in patients with renal dysfunction. Clinical applications: * Hodgkin’s and non-Hodgkin’s lymphomas. * Germ cell tumor, head and neck cancer, **_squamous cell cancer of the skin, cervix and vulva._**

Question 49

BLEOMYCIN AE:

Answer 49

Adverse effects:\*\*\*\*\*\*\*\*\*\*\* • **_Pulmonary fibrosis_** • Skin hyperpigmentation. • Mucositis _**• \*Minimal bone marrow suppression**_

Question 50

ANTHRACYCLINES Which drugs? MOA

Answer 50

Anthracyclines includes: 1) Doxo**_rubicin_** 2) Dauno**_rubicin_** MOA: * Binding to **_cellular membranes to alter fluidity and ions transport._** * Inhibition of **_topoisomerase II._** * High-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand breakage. * Generation free radicals through an iron- dependent enzyme-mediated reductive process.(cause anthracycline-associated toxicity).

Question 51

ANTHRACYCLINES AE

Answer 51

* Myelosuppression. * Mucositis. * Cardiotoxicity (treatment with the iron-chelating agent **_Dexrazoxane_** is approved to prevent or reduce anthracycline-induced cardiotoxicity). \*\*\***_Erythema and desquamation of the skin_** observed at sites of prior radiation therapy “radiation recall reaction”.\*\*\*

Question 52

DOXORUBICIN CLINICAL APPLICATION

Answer 52

ANTHRACYCLINES ## Footnote * **_One of the most important anti-cancer drugs in clinical practice_**. * Major clinical activity in cancers of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung; in soft tissue sarcomas. Used for several childhood cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma. Active in hematologic malignancies, including acute lymphoblastic leukemia, multiple myeloma, and lymphomas.

Question 53

DAUNORUBICIN CLINICAL APPLICATIONS

Answer 53

• Used in the treatment of **_acute myeloid leukemia._** **_• Limited efficacy against solid tumors._**

Question 54

ALKYLATING AGENTS KINDS? MOA

Answer 54

Alkylating agents are divided into different classes, including: **_1. Nitrogen mustards:_** such as A. Cyclophosphamide B. Ifosfamide C. Mechlorethamine D. Melphalan **_2. Nitrosoureas:_** A. Carmustine B. Lomustine **_3. Alkyl sulfonates:_** -busulfan **_4. Methylhydrazines:_** -Procarbazine **_5. Triazines:_** -dacarbazine (DTIC). Cell cycle-nonspecific drugs. Transfer of their alkyl groups (CnH2n+1) to various cellular constituents. Alkylations of DNA within the nucleus represent the major interactions that lead to cell death. The major site of alkylation within DNA is the **_N7 position of guanine._** These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups.

Question 55

ALKYLATING AGENTS ADVERSE EFFECTS

Answer 55

* **_Occur primarily in rapidly growing tissues_** such as bone marrow, gastrointestinal tract and reproductive system. * Nausea and vomiting are common. **_(pre-treatment with 5-HT3 receptor antagonists)_** They are **_potent vesicants_** and can damage tissues at the site of administration as well as produce systemic toxicity. **_Carcinogenic_** in nature, and there is an increased risk of secondary malignancies, especially acute myelogenous leukemia.

Question 56

CYCLOPHOSPHAMIDE **_Clinical applications:_** Adverse effects:

Answer 56

NITROGEN MUSTARD: ALKYLATING AGENT ## Footnote **_Clinical applications:_** Cyclophosphamide is one of the most widely used alkylating agents. Breast cancer, ovarian cancer and soft tissue sarcoma. Non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Neuroblastoma, Wilms’ tumor and rhabdomyosarcoma. AE: * Nausea and vomiting. * Bone marrow suppression. * **_Hemorrhagic cystitis_**(prevented by adequate hydration and parenteral administration of _**MESNA\*\*\*)**_

Question 57

CYCLOPHOSPHAMIDE PK

Answer 57

 Pharmacokinetics:  Can be administered via the oral and intravenous routes with equal clinical efficacy.  Activated by hepatic microsomal cytochrome P450s- including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with \*\*\*_**2B6\*\*\* displaying the highest 4-hydroxylase activity**_- which converts cyclophosphamide to 4 hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms-phosphoramide mustard and acrolein—occurs.  The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide.

Question 58

CYCLOPHOSPHAMIDE AE

Answer 58

Adverse effects: 1) Nausea and vomiting 2) Bone marrow suppression which leads to pancytpenia **_3) Hemorrhagic cystitis:_** Acrolein, a metabolite of cyclophosphamide is responsible for the hemorrhagic cystitis caused by therapy with cyclophosphamide. This can be prevented by parenteral administration of \*\*\*_**Mesna\*\*\***_, a sulfhydryl compound that **_reacts with acrolein in the bladder._** Also, ample fluid intake is recommended. Vigorous IV hydration is required during high-dose treatment.

Question 59

IFOSFAMIDE PK AE:

Answer 59

NITROGEN MUSTARD - ALKYLATING AGENT ## Footnote -MORE POTENT version of cyclophosphamide Pharmacokinetics: • A Prodrug administered via IV route. • Activated in the liver, by cytochrome p450 3A4. AE: Nausea and vomiting. Bone marrow depression. Alopecia. _**\*\*\*Nephrotoxicity.\*\*\***_ **_Hemorrhagic cystitis_** (prevented by adequate hydration and parenteral administration of **_Mesna_**). Has virtually the same toxicity profile as cyclophosphamide, although it **_causes greater_** **_1) platelet suppression,_** **_2) neurotoxicity, and_** **_3) urinary tract toxicity._**

Question 60

MECHLORETHAMINE PK:

Answer 60

NITROGEN MUSTARD - ALKYLATING AGENT ## Footnote Pharmacokinetics: * Very unstable. Solutions must be made up just prior to administration. * Largely replaced by cyclophosphamide, melphalan and other more stable alkylating agents. * **_Powerful vesicant_** (given IV only). --\> tends to cause BLISTERING

Question 61

MECHLORETHAMINE Clinical Applications AE

Answer 61

**_Clinical Applications:_** • *Hodgkin’s lymphoma.* **_Adverse effects:_** * Severe nausea and vomiting. * Severe bone marrow depression. * Alopecia. * Immunosuppression.

Question 62

MELPHALAN

Answer 62

NITROGEN MUSTARD -ALKYLATING AGENT ## Footnote Clinical applications: _**\*\*\*• Multiple myeloma. \*\*\***_ * Breast cancer. * Ovarian cancer. Adverse effects: * Bone marrow suppression. * Nausea, vomiting and diarrhea. • Oral ulceration. _**• Hepatotoxicity. • Pulmonaryfibrosis.**_

Question 63

NITROSOUREAS EXAMPLES CLINICAL APPLICATIONS AE RESISTANCE

Answer 63

ALKYLATING AGENT ## Footnote 1. CARMUSTINE (IV) 2. LOMUSTINE (ORAL) Clinical applications: The nitrosoureas are **_highly lipid-soluble_** and are able to readily **_cross the blood-brain barrier._** **_1) Brain tumors._** **_2) Lymphomas._** Adverse effects: • Myelosuppression. * Renal failure. * Pulmonary fibrosis. Resistance: • Non-cross-resistant with other alkylating agents.

Question 64

BUSULFAN

Answer 64

ALKYL SULFONATE ## Footnote Clinical applications: • Chronic myelogenous leukemia. Adverse effects: * Nausea and vomiting. * Bone marrow suppression. _**• \*\*\*Pulmonary fibrosis.\*\*\***_

Question 65

PROCARBAZINE

Answer 65

METHYLHYDRAZINE: AN ALKYLATING AGENT ## Footnote Clinical applications: • Hodgkin’s and non-Hodgkin’s lymphoma. • Brain tumors. AE: CNS depression (acute toxicity). Myelosuppression. Hypersensitivity reactions. One metabolite is a weak **_monoamine oxidase (MAO) inhibitor_**, and adverse events can occur when procarbazine is given with other MAO inhibitors as well as tyramine-containing foods. _**\*\*\*Carcinogenic potential is higher\*\*\***_ than that of most other alkylating agents (increased risk of secondary cancers in the form of acute leukemia).

Question 66

DACARBAZINE

Answer 66

TRIAZINE (alkylating agent) ## Footnote * Clinical applications: * Malignant melanoma, Hodgkin’s lymphoma, soft tissue sarcomas, and neuroblastoma. * _**\*\*\*Potent vesicant**_ \*\*\*\*(causes blisters) and care must be taken to avoid extravasation during drug administration. Adverse effects: * Myelosuppression. * Nausea and vomiting.

Question 67

PLATINUM COORDINATION COMPLEXES PK MOA

Answer 67

PLATINUM ANOLOGUES = 1) CIS**_PLATIN_** 2) CARBO**_PLATIN_** **_PK_** • Extensively cleared by the kidneys and excreted in the urine. As a result, dose modification is required in patients with renal dysfunction. **_Mechanism of action:_** * Binds DNA through the formation of intrastrand and interstrand cross-links, thereby leading to inhibition of DNA synthesis and function. * The primary binding site is the N7 position of guanine. (IE SAME AS ALL OTHER ALKYLATING AGENTS)

Question 68

CISPLATIN clinical applications AE

Answer 68

PLATINUM COMPOUND: ALKYLATING AGENT ## Footnote Clinical applications: • Major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, cholangiocarcinoma, head and neck cancer, and genitourinary cancers, \*\*\*\*_**particularly testicular, ovarian, and bladder cancer.\*\*\*\*\***_ **_AE:_** Nausea and vomiting. Mild to moderate myelosuppression. Anaphylactic-like reactions. Peripheral sensory neuropathy. Ototoxicity. Nephrotoxicity. Electrolyte disturbances: ↓ Mg+2, ↓ Ca+2, ↓ K+1and ↓ PO4-3.

Question 69

MANAGEMENT OF CISPLATIN INDUCED NEPHROTOXICITY?

Answer 69

PLATINUM COMPOUND: ALKYLATING AGNET ## Footnote Cisplatin-induced **_nephrotoxicity_** has been largely abrogated by adequate pre-treatment **_hydration and diuresis._** **_Amifostine_** is a thiophosphate **_cytoprotective agent_** indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin.

Question 70

CARBOPLATIN Clinical Applications AE

Answer 70

PLATINUM COMPOUND: ALKYLATING AGENT ## Footnote Clinical applications: • Ovarian cancer, non-small cell and small cell lung cancer, breast cancer, head and neck cancer and bladder cancer. Adverse effects: Nausea and vomiting Myelosuppression. _**\*\*\*\*Significantly less nausea, neurotoxicity, ototoxicity and nephrotoxicity (compared to cisplatin).\*\*\*\***_

Question 71

HORMONAL AGENTS 3 CLASSES

Answer 71

1) GLUCOCORTICOIDS - PREDNISONE 2) ESTEROGEN INHIBITORS A) SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs): 1. Tamoxifen 2. Raloxifene B) SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDs) 1. Fulvestrant C) AROMATASE INHIBITORS: 1. Anastrozole 2. Letrozole 3. Exemestane 3) ANDROGEN INHIBITORS A. GONADOTROPIN-RELEASING HORMONE ANALOGS 1. Goserelin 2. Leuprolide B. ANDROGEN RECEPTOR BLOCKERS -Flutamide

Question 72

PREDNISONE

Answer 72

GLUCOCORTICOID ## Footnote Induces lymphocyte apoptosis. Used against lymphocytes-drived neoplasm such as; acute lymphoblastic leukemia, lymphoma and multiple myeloma. Effective in the management of autoimmune hemolytic anemia and thrombocytopenia associated with chronic lymphocytic leukemia.

Question 73

ESTROGEN INHIBITORS CLASSES

Answer 73

1. SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERM) 2. SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDS) 3) AROMATASE INHIBITORS

Question 74

SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERM) WHAT 2 DRUGS?

Answer 74

* Bind to and activate or block estrogen receptors depending on the target tissue. * 1) TAMOXIFEN.  Has an **_anti-estrogen effect at the breast._**  _**Acts as estrogen receptors agonist at endometrium and bone. --\> \*\*\*GET ENDOMETRIAL HYPERPLASIA!!!\*\*\*\*\***_  Used in the **_prevention and treatment of breast cancer._**  Adverse effects: Hot flushes Nausea and vomiting Fluid retention Thromboembolic events Endometrial hyperplasia(risk of endometrial cancer) • 2) RALOXIFENE. **_Estrogen antagonist at the breast and endometrium_** (*no endometrial hyperplasia).*  Estrogen agonist effect at bone.  Prevention of postmenopausal osteoporosis  Prophylaxis of breast cancer in high risk postmenopausal women.  Can cause thromboembolic events

Question 75

SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDS) which drug?

Answer 75

FULVESTRANT ## Footnote Pure **_estrogen receptor antagonist_** with no agonist activity. **_Increases ER degradation._** **_Reduces the number of ER molecules in cells._** _**\*\*Used in Tamoxifen-resistant breast cancer.\*\***_

Question 76

AROMATASE INHIBITORS

Answer 76

 Inhibit aromatase enzyme which is **_required for estrone synthesis from androstenedione._**  Estrone is the primary estrogen in postmenopausal women.  **_Used as Adjuvant chemotherapy in estrogen receptor positive breast cancer._** **_KNOW THIS:_** **A) Anastrozole and Letrozole** are NONSTEROIDAL COMPETITIVE **_inhibitor of aromatase_** **_B) Exemestane_** is a **_STEROIDAL_** and **_IRREVERSIBLE inhibitor of aromatase._**

Question 77

ANDROGEN INHIBITORS KINDS?

Answer 77

**_1) ANDROGEN RECEPTOR BLOCKERS_** EG) FLUTIMIDE **_2) GONADOTROPIN-RELEASING HORMONE ANALOGS_** EG) 1) Goserelin. 2) Leuprolide.

Question 78

FLUTAMIDE

Answer 78

* Non-steroidal, **_competitive antagonist_** at the **_androgen receptor._** * Used in the **_treatment of prostatic carcinoma._** * Frequently causes mild gynecomastia. * Occasionally cause reversible hepatic toxicity.

Question 79

GONADOTROPIN-RELEASING HORMONE ANALOGS

Answer 79

1) GOSERELIN 2) LEUPROLIDE ## Footnote **_Pulsatile_** administration stimulates FSH and LH release from anterior pituitary. These gonadotropins stimulate the release of gonadal hormones.  **_Continuous_** administration of GnRH analogs produces a **_biphasic response:_** **_1. initial phase (flare):_**  During the first 7–10 days of continuous GnRH analogs administration.  Characterized by increased concentrations of gonadal hormones production. **_(INCREASED LH, FSH, + TESTOSTERONE)_**  This phase can be effectively counteracted with concurrent administration of **_Flutamide_** for 2- 4 weeks (see below). (PLAY THE FLUTE TO DECREASE YOUR MANLYNESS) **_2. Delayed phase: DECREASED LH, FSH, TESTOSTERONE_**  Continuous presence of GnRH analogs results in an inhibitory action that manifests as 1) a drop in the concentration of gonadotropins and gonadal steroids (ie, hypogonadotropic hypogonadal state). 2) The inhibitory action is due to a combination of receptor down-regulation and changes in the signaling pathways activated by GnRH. **_Continous administration of GnRH analogs is used against PROSTATE CANCER._** Can cause Impotence, hot flashes and testicular atrophy.

Question 80

SIGNAL TRANSDUCTION INHIBITORS

Answer 80

``` This class includes: 1. Inhibitors of **_EGFR (ErbB1) and HER2/neu (ErbB2)._** ``` 2. Inhibitors of **_BCR-ABL & C-KIT._** 3. Inhibitors of **_RAS/MAP kinase pathways._** 4. **_Proteasome Inhibitors._** 5. **_Angiogenesis Inhibitors._** * Cancer is driven by genetic and epigenetic alterations, which lead to uncontrolled cell proliferation and tumorigenesis . * Many of these alterations involve the cell signaling pathways. * **_Signal transduction_** (cell signaling) is the transmission of molecular signals from a cell's exterior to its interior. * Signals received by cells must be transmitted effectively into the cell to ensure an appropriate response. * This process is initiated by cell-surface receptors. * Protein kinases are critical components of signal transduction pathways that regulate cell growth and adaption to the extracellular environment. * Protein kinases can be classified into: 1. Tyrosine kinases. 2. Serine and Threonine kinases. 3. kinases with activity toward all three residues.

Question 81

GEFITINIB

Answer 81

INHIBITOR OF EGFR TYROSINE KINASE ## Footnote -used for SMALL CEL LUNG CANCER

Question 82

ERLOTINIB

Answer 82

-INHIBITOR OF THE EGFR TYROSINE KINASE ## Footnote USES: 1) NON-SMALL CELL LUNG CANCER 2) CARCINOMA OF PANCREAS

Question 83

CETUXIMAB

Answer 83

MONOCLONAL ANTIBODY VS. EGFR ## Footnote -USED FOR **_COLORECTAL CANCER_** --\> efficacy of cetuximab is restricted to patients with tumors expressing **_WILD-TYPE KRAS_**) -head and neck cancer also

Question 84

LAPATINIB

Answer 84

INHIBITOR OF EGFR **_+ ERB-B2_** **_Clinical applications:_** **_1) non-small cell lung cancer_** **_2) CARCINOMA OF PANCREAS_**

Question 85

TRASTUZUMAB

Answer 85

HUMANIZED MONOCLONAL ANTIBODY AGAINST ERbB2 (HER2) ## Footnote USES: 1) BREAST CANCER WITH HER2 OVEREXPRESSION 2) **_CARDIOTOXICITY_**

Question 86

IMATINIB

Answer 86

MOA: Inhibits the of Bcr-Abl tyrosine kinase. Inhibits c-kit (receptor tyrosine kinase). CLINICAL APPLICATIONS: _**1) CML\*\*\*\* 2) Kit-positive Gastrointestinal stromal tumor**_.\*\*\*\* **_3) Idiopathic hypereosinophilic syndrome_**

Question 87

SORAFENIB

Answer 87

1) Inhibits the **_RAF serine/threonine kinase._** 2) Inhibits **_VEGF-R2 and VEGF-R3, PDGFR-β._** **_USES:_** **_1) RENAL CELL CARCINOMA_**

Question 88

BORTEZOMIB

Answer 88

moa: PROTEASOME INHIBITOR --\> **_Induces growth inhibition and apoptosis of tumor cells._** **_Clinical applications:_** 1) MULTIPLE MYELOMA 2) MANTLE CELL LYMPHOMA

Question 89

SUNITINIB

Answer 89

- INHIBITS **_ANGIOGENESIS_** - Inhibits VEGFR-1, VEGFR-2, and PDGFR **_• Clinical Applications:_** • Renal cell carcinoma. • Gastrointestinal stromal tumor.

Question 90

ASPARAGINASE MOA CLINICAL APPLICATION AE

Answer 90

**_ Mechanism of Action:_**  Asparaginase (Aka L-asparagine amidohydrolase) _***hydrolyzes circulating L-asparagine to aspartic acid and ammonia*.**_  Because *tumor cells in ALL* lack asparagine synthetase, they _require an exogenous source of L-asparagine_. **_Thus, depletion of L-asparagine results in effective inhibition of protein synthesis_**. In contrast, normal cells can synthesize L-asparagine and thus are less susceptible to the cytotoxic action of asparaginase. **_Clinical application:_**  ***_Childhood acute lymphoblastic leukemia (ALL)._*** **_Adverse effects:_**  Hypersensitivity.  Decrease in clotting factors.  Liver abnormalities.  Pancreatitis.  Seizures and coma.

Question 91

HYDROXYUREA moa clinical applications adverse effects

Answer 91

**_Mechanism of Action:_**  \*\*\*_**Inhibits ribonucleotide reductase\*\*\***_ which converts ribonucleoside diphosphate to deoxyribonucleosides diphosphate  This **_leads to depletion of deoxyribonucleosides trisphosphate pool._** DNA synthesis is thereby inhibited.  Kills cells in S phase. **_Clinical applications:_**  Malignant melanoma  Chronic myelocytic leukemia  Ovarian cancer.  Primary squamous cell carcinomas of the head and neck, excluding the lip.  Hydroxyurea is also used in the treatment of adult sickle cell disease (increases the level of hemoglobin F). **_Adverse effects:_** _** Myelosuppression\*\*\*\*\*\***_  Nausea, vomiting and diarrhea.  Skin rash and hyperpigmentation.  Macrocytosis

Question 92

INTERFERON ALPHA MOA CLINICAL APPLICATIONS AE

Answer 92

**_Mechanism of Action:_**  Stimulates natural killer cells to kill the transformed cells  Increases the expression of HLA molecules on tumor cells **_Clinical applications:_**  Kaposi sarcoma  Hairy cell leukemia  Renal cell carcinoma  Antiviral activity against HPV (condylomata acuminata), HBV and HCV. **_Adverse effects:_**  Flu like symptoms

Question 93

CHEMOMAN

Answer 93