Principles Of Cancer Chemotherapy

Front 1

*What are the 3 different growth classes of cells that comprise a tumor?

Back 1

1) Renewing (dividing)
2) Expanding (temporarily non-dividing)
3) Static (permanently non-dividing)

Front 2

*What cells are dividing cells (Renewing)?

Back 2

Gametes, blood cells, epidermis, GI tract

Front 3

*What cells are static?

Back 3

Striated muscles and neurons
-Why neuronal damage is so bad

Front 4

*What cells are expanding cells?

Back 4

Glands, liver, kidney
-Can't renew but can expand in times of stimulation

Front 5

What cells do tumors arise from?

Back 5

A single stem cell with the ability to divide (clonogenic)

Front 6

True or false. All daughter cells of a tumor retain the ability to reproduce the tumor.

Back 6

False, not all daughter cells (clones) retain the ability to reproduce the tumor.

Front 7

What is necessary to cure cancer?

Back 7

All stem cells must be eradicated.

Front 8

How does metastases occur?

Back 8

Stem cell migration

Front 9

What is the growth fraction (GF)?

Back 9

The proportion of proliferating cells in a tumor.

Front 10

What is the mitotic index (MI)?

Back 10

The fraction of cells in mitosis in a tumor.

Front 11

What is the doubling time?

Back 11

The time required for the cell population and tumor volume to double.

Front 12

What does the tumor growth rate reflect?

Back 12

Growth fraction
Cell cycle duration
Loss of cells due to death and metastases

Front 13

Gompertzian growth of tumors means that tumor growth is ________.

Back 13

Exponential, with a growth constant that is exponentially decreasing.

Front 14

According to Gompertzian growth of tumors, as a tumor increases in size, what happens to the doubling time?

Back 14

Becomes progressively longer

Front 15

According to Gompertzian growth of tumors, what is the relative growth fraction and mitotic index of large tumors? Small tumors?

Back 15

Large tumors: low growth fraction & mitotic index
Small tumors: high growth fraction & mitotic index

Front 16

Large tumors contain more cells in what stage of the cell cycle compared to small tumors?

Back 16

G0-resting stage

Front 17

Most normal tissues have a ______ growth fraction, ______ mitotic index and ________ doubling time. What's the exception?

Back 17

Low GF
Low MI
Prolonged DT
Exception: bone marrow cells and intestinal crypt eptihelium have high growth fraction & mitotic index

Front 18

What happens to tumor kinetics after debulking is performed?

Back 18

May change growth rate by recruitment of cells into the mitotic cycle, resulting in a high growth fraction, mitotic index and a shortened doubling time
-Why you start chemotherapy immediately after debulking

Front 19

What is the cell-kill hypothesis?

Back 19

The number of tumor cells killed by a drug or drug combination is proportional to only variable, the dose used.

Front 20

What type of kinetics is the cell-kill hypothesis of chemotherapy?

Back 20

First order kinetics-chemotherapy kills a certain proportion of cells, not a certain number.

Front 21

**What are the 2 clinical implications of first order kinetics as they pertain to treatment with anticancer drugs?

Back 21

1) Chemotherapy should be instituted when tumor burden is minimal (e.g. immediately post surgery)
2) Maximal doses of drugs should be given (only variable that affects the number of tumor cells killed)

Front 22

True or false. "Resting" cells are commonly the target of chemotherapy.

Back 22

False, most agents affect DNA synthesis or function

Front 23

*What is a cell cycle (phase)-specific drug?

Back 23

Agents that act within a single phase of the cell cycle.
e.g. antimetabolites & plant alkaloids

Front 24

*When are cell cycle (phase)-specific anticancer drugs most effective?

Back 24

In tumors with a high growth fraction

Front 25

*What are cell cycle (phase)-nonspecific drugs?

Back 25

Agents that kill cells regardless of their phase in the cell cycle, but the cytotoxicity depends upon a cell that either attempts division or DNA-repair.
e.g. Alkylating agents, antitumor antibiotics

Front 26

*True or false. Cell cycle (phase)-nonspecific drugs require a high growth fraction to be effective.

Back 26

False, that's only cell cycle specific drugs

Front 27

*What are cell cycle nonselective drugs?

Back 27

Agents that can kill cells independent of their resting or dividing status

Front 28

*What is a serious side effect of cell cycle nonselective drugs?

Back 28

Potent inhibitors of pluripotent bone marrow stem cells and cause severe, prolonged myelosuppression

Front 29

**What alkylating agent is most important in veterinary medicine?

Back 29

Cyclophosphamide (Cytoxan)
-Used for lymphoma, leukemia, multiple myeloma, carcinoma soft tissue sarcomas

Front 30

**What are the 6 major classes of anticancer drugs?

Back 30

1) Alkylating agents
2) Antimetabolites
3) Antitumor antibiotics
4) Plant alkaloids
5) Adrenal corticosteroid hormones
6) Miscellaneous

Front 31

*What is the mechanism of action of alkylating agents?

Back 31

Insert alkyl groups that cross link the DNA so the DNA can't separate for replication.
-Same effect as radiation so terms radiomimetic

Front 32

*What is the mechanism of action of antimetabolites?

Back 32

Structural analogues of normal metabolites needed for purine and pyrimidine biosynthesis (and therefore DNA replication)

Front 33

*True or false. Alkylating agents are cell cycle nonspecific drugs.

Back 33

True

Front 34

*True or false. Antimetabolites are cell cycle nonspecific drugs.

Back 34

False, they are cell cycle specific and are most effective on cells in the S phase

Front 35

How are antitumor antibiotics produced?

Back 35

By microbial fermentation

Front 36

*What is the mechanism of action of anthracycline antibiotics?

Back 36

Intercalate adjoining nucleotide pairs, therefore inhibiting DNA and RNA synthesis.

Front 37

*True or false. Antitumor antibiotics are cell cycle nonspecific drugs.

Back 37

True

Front 38

What is the most important antitumor antibiotic?

Back 38

Doxorubicin
-Other two antibiotics: bleomycin and actinomycin-D

Front 39

How are plant alkaloids produced?

Back 39

Compounds extracted from the periwinkle plant and May apple plant.

Front 40

*What is the mechanism of action of plant alkaloids?

Back 40

Produce mitotic spindle toxicity by damaging the microtubular spindle proteins, resulting in metaphase arrest

Front 41

*True or false. Plant alkaloids are cell cycle nonspecific drugs.

Back 41

False, they are most active during mitosis (M phase)

Front 42

*What are the 2 roles of adrenal corticosteroid hormones in cancer treatment?

Back 42

1) Direct destruction of tumor cells with steroid receptors-plasma cells, mast cells, lymphocytes
-Very specific
2) Control of paraneoplastic syndromes such as immune mediated hemolytic anemia, thrombocytopenia, hypercalcemia

Front 43

**What cells are destroyed when using adrenal cortisteroid hormones for chemotherapy?

Back 43

Only cells that possess a steroid receptor-plasma cells, lymphocytes, mast cells

Front 44

*What is the mechanism of action of adrenal corticosteroid hormones used for chemotherapy?

Back 44

Steroid activated endonucleases disrupt nuclear DNA, triggering apoptosis.

Front 45

What are the steroids of choice for chemotherapy?

Back 45

Prednisone (dogs-converted to prednisolone in liver)
Prednisolone (cats)

Front 46

*What is different about the distribution of corticosteroids compared to other cancer medication?

Back 46

Can cross the blood brain barrier so important in treatment of CNS lymphoma/leukemia

Front 47

What steroid is preferred for CNS malignancy? Why?

Back 47

Dexamethasone because less protein bound and more bioavailable to brain

Front 48

What drug is analogous to alkylating agents?

Back 48

Cisplatin

Front 49

*What is the mechanism of action of cisplatin?

Back 49

Covalently binds nucleotides, especially guanine, resulting in inter- and intrastrand DNA cross-links preventing DNA separation.

Front 50

True or false. Cisplatin is a cell cycle nonspecific drug.

Back 50

True

Front 51

*What is the mechanism of action of carboplatin?

Back 51

A second generation version of cisplatin (cross links DNA)

Front 52

Why is carboplatin used in place of cisplatin?

Back 52

Its not nephrotoxic and can be given as a bolus injection w/o prolonged diuresis which accompanies cisplatin treatment

Front 53

What is L-asparaginase?

Back 53

Enzyme product of E. coli

Front 54

*What is the mechanism of action of L-asparaginase?

Back 54

Enzyme that converts plasma asparagine to nonfunctional aspartic acid, thereby blocking protein synthesis.

Front 55

*What is metronomic dosing of chemotherapeutic agents?

Back 55

Continuous administration of very small doses of cytotoxic agents.

Front 56

*What type of anticancer drug is most commonly given using metronomic dosing?

Back 56

Alkylating agents e.g. cyclophosphamide

Front 57

*What are the 2 goals of metronomic dosing?

Back 57

1) Anti-angiogenic effect: inhibition of dividing endothelial cells in the tumor microenvironment to minimize formation of new blood supply to growing tumor.
2) Immunostimulatory effect: reduce the number of T-regulatory T cells that act to down modulate cell-mediated immune responses important in cancer.

Front 58

True or false. Metronomic dosing has relatively high toxicity.

Back 58

False, relatively low toxicity-small doses

Front 59

How can the anti-angiogenic effects of metronomic dosing be enhanced?

Back 59

Giving non-steroidal anti-inflammatory drugs and doxycycline in combination w/ the low dose cytotoxic drug

Front 60

True or false. Chemotherapy can be used as a substitute for surgery or radiotherapy.

Back 60

False

Front 61

*What are 4 indications of chemotherapy?

Back 61

1) Primary used for systemic (e.g. lymphoma) and metastatic neoplasms
2) Can be used for nonresectable, drug-responsive tumors (mast cell tumors or tumors that have failed radiotherapy), may reduce to a size that is more operable.
3) Adjuvant treatment following incomplete surgical excision
4) Control of micrometastatic disease following excision of a tumor with known metastatic potential (e.g. osteosarcoma, hemangiosarcoma)

Front 62

When is chemotherapy contraindicated?

Back 62

In patients w/ severe underlying multiple organ dysfunction bc can compound systemic abnormalities

Front 63

*What plant alkyloid is most commonly used in veterinary medicine? What's it used for?

Back 63

Vincristine-lymphoma, soft tissue sarcoma

Front 64

*What are 4 anti-metabolites commonly used in vet med?

Back 64

1. Cytosine arabinoside
2. 5-fluorouracil (carcinoma)
3. Methotrexate
4. Azathioprine (used for IMHA)

Front 65

What causes acquired drug resistance?

Back 65

The result of positive selection pressure exerted by chemotherapy, allowing resistant cells to re-populate

Front 66

What are some mechanisms of acquired drug resistance?

Back 66

-Defective drug transport
-Defective drug metabolism
-Altered intracellular nucleotide pools
-Increased drug inactivation
-Altered DNA repair
-Gene amplification
-Altered target proteins

Front 67

What is pleiotropic drug resistance?

Back 67

Acquired resistance of tumor cells to multiple chemotherapeutic agents after exposure to only a single drug
-A type of acquired resistance

Front 68

What is natural resistance?

Back 68

Spontaneous mutations of tumor cells results in emergence of new clones which are naturally resistant to some anticancer drugs

Front 69

How should cell cycle phase-specific drugs be administered?

Back 69

In fractionated schedules or infusions (unless they have a long half life)

Front 70

How should cell cycle phase-nonspecific drugs be administered?

Back 70

As a single large doses in intermittent schedules (unless employed in a metronomic protocol)

Front 71

*What are the primary indications for chemotherapy?

Back 71

Systemic (e.g. lymphoma) and metastatic neoplasms

Front 72

What is the mechanism of action of DTIC?

Back 72

Appears to resemble both an alkylating agent and antimetabolite action.

Front 73

What is DTIC used for?

Back 73

Possesses some activity against malignant melanoma and lymphoma when combined w/ doxorubicin.

Front 74

What is the hallmark of a doxorubicin reaction (hypersensitivity)?

Back 74

Head shaking and ear pinna is red