Cancer Chemotherapy Drugs

Front 1

Antimetabolites
(Mechanism)

Back 1

1. generally interfere with nucleic acid biosynthesis
2. They "look like" folic acid, pruines, and pyrimidines

*Drugs - Folate Analogs, Pyrimidine Analogs, Purine Analogs, Ribonucleotide Reductase Inhibitor*

Front 2

Alkylating Agents
(Mechanism)

Back 2

1. covalently bind to DNA
2. damages genomic material and ultimately effects DAUGHTER CELLS
3. Neucleophilic attack

*Drugs - Nitrogen Mustards, Nitrosoureas, Platinum Compounds, Azidines, Alkyl Sulfonates, Methylating Agents*

Front 3

Antitumor Antibiotics
(Mechanism)

Back 3

1. disrupt DNA structure and function

Front 4

Antimitotic Agents
(Mechanism)

Back 4

1. block topoisomerase or microtubule functions

Front 5

Hormonal Agents
(Mechanism)

Back 5

1. affect signaling through steroid receptors

Front 6

Signaling Inhibitors
(Mechanism)

Back 6

1. block critical signaling pathways in cancer cells

Front 7

Hematopoeitic Growth Factors
(Mechanism)

Back 7

1. promote the recovery of blood cells after chemotherapy

Front 8

Discuss the "log-kill" hypothesis...

Back 8

1. repetitive/intermittent therapy necessary to utilize the FIRST ORDER kinetics of chemotherapy agents

Front 9

Define Adjuvant vs. Neoadjuvant therapy:

Back 9

1. Adjuvant therapy - use drugs after surgery to remove residual or metastatic cells
2. Neoadjuvant therapy - use drugs before surgery to reduce tumor mass and to initiate chemotherapy sooner

Front 10

At which phase of the cell cycle does DNA synthesis occur?

Back 10

1. Between G1 and G2 during the S phase

Front 11

Define Autophagy:

Back 11

1. Normal programmed cell death or apoptosis which is a future target of cancer chemotherapy (some cancers block autophagy leading to uncontrolled growth)

Front 12

Cell phase-specific drugs:
(used to treat what kinds of tumors, which phase is not useful, which catagories of agents does it include?)

Back 12

1. treats tumors with very high turnover
2. does not effect cells in the G0 phase
3. includes antimetabolites, topoisomerase inhibitors, and antimitotic agents

**these agents have cytotoxic activity seen is a specific phase of the cell cycle and are SCHEDULE DEPENDENT**

Front 13

Cell phase-nonspecific drugs:
(used to treat what kinds of tumors, which phase is not useful, which catagories of agents does it include?)

Back 13

1. used to treat large tumors with LOW GROWTH RATES
2. Effective against those in G0 phase
3. Includes alkylating agents and anthracyclines

**these agents kill cells regardless of the phase of the cell cycle and they are DOSE-DEPENDENT**

Front 14

What are the pharmacokinetics of chemotherapeutic agents?

Back 14

1. FIRST ORDER

100 cells --> 50 cells
10,000 cells --> 5,000 cells
100,000 cells --> 50,000 cells

*consistent percentage of cells killed*
*but we want "log-kill" drugs that kill 90% or more!*

Front 15

What is the major mechanism of resistance to cancer drugs?

Back 15

1. Increased EFFLUX of the drug from the MDR ATPase pump

**upregulation of this MDR gene increases resistance**

Front 16

What would you consider when selecting combination chemotherapy?

Back 16

1. drugs that have antitumor activity when used alone
2. non-overlapping toxicities
3. target different phases of the cell cycle
4. different mechanisms of action
5. different mechanisms of resistance

Front 17

Methotrexate
(Class, mechanism, what is used in combination with it)

Back 17

1. member of ANTIMETABOLITE class
2. Competitive inhibitor of folic acid - which is a methyl transferase (but it blocks the "NADPH recycling step)
3. Leukovorin - synthetic folic acid that non-cancer cells take up for use (rescue)

Front 18

5-Fluorouracil
(Class, mechanism)

Back 18

1. ANTIMETABOLITE
2. inhibits Thymidate Synthase (dUMP --> dTMP) which stops DNA synthesis in another way
3. irreversible binding

Front 19

6-Mercaptopurine
(Class, mechanism)

Back 19

1. ANTIMETABOLITE
2. Purine Analogue

**ATP - energy currnecy, GTP - second messenger**

Front 20

Hydroxyurea
(Class, mechanism, resistance)

Back 20

1. ANTIMETABOLITES
2. destabilizes the iron center at the active site of RR (NDP --X--> dNDP)
3. Increased levels of ribonucleotide reductase leads to resistance

Front 21

What are the 2 major classes of "natural products"?

Back 21

1. Microtubule Inhibitors
2. Topoisomerase Inhibitors

Front 22

What is the function of microtubules?

Back 22

1. necessary for the proper function of the mitotic spindle, they're always growing and shortening
2. Disruption leads to APOPTOSIS

Front 23

Vinca alkaloids
(Class, mechanism)

Back 23

1. Microtubule Inhibitors
2. Bind to TUBULIN and inhibit formation of microtubules

Front 24

Taxanes
(Class, mechanism)

Back 24

1. Microtubule Inhibitors
2. Taxol binds to the already assembles MTs and PREVENTS BREAKDOWN OF THEM... if they can't be broken down, the cell will apoptose as well

Front 25

Estramustine
(Class, mechanism, resistance)

Back 25

1. MT inhibitors
2. initially designed as an alkylating agent, but binds to MTs
3. Tubulin mutations and increased efflux

**most active in M phase**

Front 26

Topoisomerase II inhibitors
(function of topoisomerase II, mechanism of drug)

Back 26

1. required for DNA unwinding during replication
2. binds to the topo II-DNA complex and causes PERMANENT DOUBLE STRAND BREAKS

*happens in the S phase of the cell cycle*
**BLOCKS FORMATION of daughter chromosomes**

Front 27

Topoisomerase I inhibitors
(function of topoisomerase I, mechanism of drug)

Back 27

1. catalyzes single strand breaks to relieve torsional stress
2. binds to topoisomerase I-DNA complex and PREVENTS RELIGATION of the DNA strand

*happens during the S phase of the cell cycle*
**BLOCKS FORMATION of daughter chromosomes**

Front 28

Anthracyclines
(Class, mechanisms (3))

Back 28

1. ANTITUMOR ANTIBIOTICS
2. Intercalation into the DNA itself causing local uncoiling of the double helix... can also cause double and single strand breaks from the topoisomerases
3. Generate O2 free radicals
4. Bind to cell membrane and screw up signal transduction pathways and transport mechanisms

**tend to be flat, polycyclic, hydrophobic, "nasty" molecules that come readily into the cell**

Front 29

L-Asparaginase
(Class, mechanism)

Back 29

1. ANTITUMOR ANTIBIOTIC
2. depletes plasma levels of Asparagine causing selective inhibition of tumor cells

**neoplastic cells have low AS (asparagine synthetase)**

Front 30

Glucocorticoids - Hormonal agent

Back 30

1. block synthesis of key regulatory elements by binding to intracellular signal receptors
2. used to treat Leukemia and Lymphoma
3. many side effects
4. resistance by decreased GR expression or mutation
5. toxic to T-cells

Front 31

Progestins - Hormonal agent

Back 31

1. Used against advanced endometrial cancer
2. agonist for progesterone receptors

Front 32

Antiestrogens (Tamoxifen) - Hormonal agents

Back 32

1. ER antagonist (estrogen reductase?)
2. used to treat breast cancer in post-menopausal women
3. metabolized by p450 enzymes
4. resistance acquired by mutation or decreased expression of ER

**estrogen synthesis in post-menopausal women takes place in adipose tissue, not ovaries**

Front 33

Aromatase Inhibitors - Hormonal agents

Back 33

1. used in advanced breast cancer in post-menopausal women
2. needs multiple steps by p450s before active form

**estrogen synthesis in post-menopausal women takes place in adipose tissue, not ovaries**

Front 34

Antiandrogens - Hormonal agents

Back 34

1. androgen receptor antagonist
2. used to prevent prostate cancer
3. used with LHRH agonist

Front 35

GnRH analogs (LHRH analogs) - Hormonal agents

Back 35

1. Used for prostate cancer along with antiandrogens

Front 36

This category of chemotherapeutic agent is typically referred to as "biologics" and are thought to be related to immune system stimulation.

Back 36

1. Cytokines
2. Drugs - Interferon Alpha, IL-2

Front 37

IL-2
(pharmacokinetics, toxicities)

Back 37

1. VERY short half-life (13 mins)
2. can be either conitnuous or intermittent infusion
3. many have long term response to this therapy (5-10% 5 yr. disease free)
4. Vascular leakage, Inflamation, Arrythmias, fever, chills, PULMONARY EDEMA

Front 38

Interferon Alpha
(biological function, mechanism, toxicities)

Back 38

1. Cell surface receptors that stimulate immune activities (phagocytosis and T-cell activation)
2. flu-like symptoms
**name given due to its ability to "interfere" with viral RNA and protein synthesis**

Front 39

Drugs that end in "ib" typically do what?

Back 39

1. They're small molecules that inhibit protein kinases

Front 40

Drugs that end in "mab" typically do what?

Back 40

1. They're monoclonal antibodies that have the same target (protein kinases) but are not limited to them

Front 41

What are the 3 types of SIGNALING INHIBITORS?

Back 41

1. Protein Kinase Inhibitors
2. Angiogenesis Inhibitors
3. Proteosome Inhibitors

Front 42

Imatinib
(Class, mechanism, why is it so good?)

Back 42

1. Signaling Inhibitor (Protein Kinase inhibitor)
2. Inhibits Bcr-Abl tyrosine kinase activity (from PHILADELPHIA CHROMOSOME TRANSLOCATION)
3. This activity is SPECIFIC to these cancerous cells.. treatment is 90% effective

Front 43

Gelfinitib
(Class, mechanism)

Back 43

1. Signaling Inhibitors (Protein Kinase Inhibitors)
2. Competitor for the ATP binding site for EFGR

Front 44

Erlotinib
(Class, mechanism)

Back 44

1. Signaling Inhibitors (Protein Kinase Inhibitors)
2. Competitor for ATP binding site for EFGR
3. Pneumoitis (can be deadly)

**greatly improves one year survival rate**

Front 45

Trastuzumab
(Class, mechanism)

Back 45

1. Antibody that binds to the HER2 protein (expressed in 30% of breast cancers)
2. increases cellular cytotoxicity towards overexpressing tumor cells
3. Signaling Inhibitors (Protein Kinase Inhibitors)

*first antibody therapy for cancer*

Front 46

Cetuximab
(Class, mechanism, tox)

Back 46

1. Signaling Inhibitors (Protein Kinase Inhibitors)
2. Monoclonal Antibody that binds EGF receptors (external cellular domain)
3. Acne-like rash on skin

Front 47

Rituximab
(Class, mechanism)

Back 47

1. Signaling Inhibitors (Protein Kinase Inhibitors)
2. Ab that binds the CD20 antigen (expressed on most B-cells in NON-HODGKIN'S LYMPHOMAS and LEUKEMIAS)
3. Binding directly inhibits cell activation and cell cycle progression and directs cytotoxicity toward the overexpressing tumor cells

Front 48

Bevacizumab
(Class, mechanism, tox)

Back 48

1. Signaling Inhibitors (Angiogenesis Inhibitors)
2. BINDS VEGF - Doesn't target the tumor itself, but inhibits it's "support system" (inhibits new blood vessel formation
3. Impaired healing, hemorrhage (hemoptysis)

**approved for treatment in advanced colon cancer with 5-FU**

Front 49

Bortezomib
(Class, mechanism)

Back 49

1. Signaling Inhibitors (Proteosome Inhibitors)
2. Inhibits proteosome formation in dividing cells (not as much of a problem in non-dividing cells) - Specific and reversible inhibitor... normal cells arrest, then recover..

Front 50

With regard to treatment, what are the major classes of hematologic malignancies (7)

Back 50

1. Hodgkin's Disease (Lymphoma)
2. Non-Hodgkin's Lymphoma
3. ALL
4. AML
5. CLL
6. CML
7. Myeloma

Front 51

Which 3 "acronym" treatments would you use in Hodgkin's Disease (Lymphoma)?

Back 51

1. ***ABVD***
2. Stanford V
3. BEACOPP

Front 52

What drugs are used in treatment of Hodgkin's Disease?
(A......)

Back 52

***ABVD***
1. Adriamycin (aka - Doxorubicin, Hydroxydaunarubicin)
2. Bleomycin
3. Vincristine (aka - Oncovin)
4. Dacarbazine

Front 53

Name the 3 MOA's of anthracyclines and name the 3 drugs for the class.

Back 53

MOA's
1. Intercalation into DNA
2. Generation of free radicals
3. Disrupts cell signal transduction by binding cell membrane

Front 54

Bleomycin
(MOA, class)

Back 54

1. Intercalation into DNA and binding heavy metal ions (Cu/Fe)
2. Natural products

Front 55

Dacarbazine
(MOA, class)

Back 55

1. Covalently crosslinks proteins RNA and DNA at N-7 position. Leads to base mispairing and strand breakage (activated by CYP450)
2. Alkylating agent

Front 56

Drug regimen for Hodgkin's Disease
(S..........)

Back 56

***Stanford V***
1. Mechlorethamine
2. Doxorubicin
3. Vinblastine
4. Vincristine
5. Bleomycin
6. Etoposide
7. Prednisone

**more rigorous than ABVD - not first line treatment**

Front 57

Drug regimen for Hodgkin's Disease
(B..........)

Back 57

***BEACOPP***
1. Bleomycin
2. Etoposide
3. Adriamycin (Doxorubicin, anthracycline)
4. Cyclophosphamide
5. Oncovin (Vincristine)
6. Procarbazine
7. Prednisone

**first line in Europe - more rigorous than ABVD**

Front 58

How do you decide how to treat the different classes of Non-Hodgkin's Lymphoma?

Back 58

1. Separate them into Indolent - low grade (incurable but slow) OR Intermediate - High grade (aggressive, but curable)

Front 59

What is the most common "indolent - low grade" Non-Hodgkin's lymphoma?
What is the most common way to treat it?
(C.......)

Back 59

1. Follicular lymphoma
2. CHOP + rituximab
Cyclophosphamide
Hydroxydaunarubicin (doxorubicin, adriamycin)
Oncovin (Vincristine)
Prednisone
Rituximab

Front 60

What is another treatment regimen for NHL?
(FND+R)
...and what are their MOAs?

Back 60

1. Fludarabine (purine analog that inhibits DNA pol, ribonucleotide reductase, DNA primase and ligase plus incorporated into DNA
2. mitoxantrone ( Topo II inhibitor)
3. Dexamethasone (Synthetic glucocorticoid - immunosupressant)
4. Rituximab (monoclonal ab)

Front 61

Bendamustine
(What is it?)

Back 61

1. Purine coupled to a nitrogen mustard thats recently been approved

Front 62

Name and describe the 3 phases of therapy with ALL

Back 62

1. Induction - Multiple drugs in an aggressive manner to achieve a CR
2. Consolidation - rigorous therapy using different drug coctail to minimize resistant cells
3. Maintenance - low dose monthly therapies to maintain remission (3 yrs)

Front 63

In ALL, what drugs would you use in "induction therapy"?

Back 63

1. Vincristine
2. Dexamethasone
3. L-Asparaginase
4. Intrathecal therapy to prevent CNS attack (Methotrexate or Cytarabine)

Front 64

In ALL, what drugs would you use in "consolidation therapy"?

Back 64

1. Methotrexate (high doses), can be with or without L-Asparaginase
2. Try to avoid anthracyclines and alkylating agents, but if at risk patient, use a short course of them in combination with high MTX w/ Leucovorin

Front 65

In ALL, what drugs would you use for "maintenance therapy"?

Back 65

1. MTX
2. 6-Mercaptopurine

Front 66

What drugs would you use to treat AML?

Back 66

1. Cytarabine
2. Idarubicin or Daunarubicin
3. HSCT
4. All-trans-retinoic acid (in APL)

Front 67

What drugs would you use to treat CLL?

Back 67

1. Watchful waiting
2. Fludarabine plus Rituximab
3. Cyclophosphamide
4. Vincristine
5. Prednisone
6. Chlorambucil with prednisone (old way to do it)
7. Alemtuzumab (new drug)

Front 68

What drugs would you use to treat CML?

Back 68

1. Imatinib (for Ph chrom +)
2. Dasatinib
3. Nilotinib
4. HSCT
5. Interferon alpha

**different treatment in blast crisis**
Lymphoid?
- ALL-like induction therapy plus dasatinib
Myeloid?
- AML-like induction therapy plus dasatinib

Front 69

How would you treat Multiple Myeloma?

Back 69

1. Bortezomib
2. Thalidomide with Dexamethasone
3. Vincristine
4. Adriamycin (doxorubicin, dexamethasone)
5. Cyclophosphamide with prednisone

Front 70

Bortezomib (Velcade)
(MOA)

Back 70

1. Specific and reversible inhibitor of proteosome activity. Proteosomes degrade proteins involved in regulation of the cell cycle, apoptosis, and angiogenesis. Normal cells arrest and recover from transient inhibition, however cells taht are overproliferative cannot and apoptose