8: Cancer Lecture I

Question 1

Cancer is the ______ leading cause of death & pancreatic cancer is one of the most ______. Also, cancer incidence and deaths are ______ as a function of time.

Answer 1

Cancer is the second leading cause of death & pancreatic cancer is one of the most malignant. Also, cancer incidence and deaths are increasing as a function of time.

Question 2

Oncogenes need damage to ______ allele to get a gain of function mutation to express the disease.

Answer 2

Oncogenes need damage to one allele to get a gain of function mutation to express the disease.

Question 3

Tumor suppressor genes need ______ alleles to be damaged to get a loss of function to express the disease.

Answer 3

Tumor suppressor genes need two alleles to be damaged to get a loss of function to express the disease.

Question 4

By the time the earliest detection of cancer occurs there are ______ doublings; hence, early detection is key.

Answer 4

By the time the earliest detection of cancer occurs there are 30 doublings; hence, early detection is key.

Question 5

Anticancer agents mediate their effects by inducing Cell Cycle ______ and/or Cell ______. Certain drugs act in specific phase of the cell cycle while others are phase nonspecific.

Answer 5

Anticancer agents mediate their effects by inducing Cell Cycle Arrest and/or Cell Death (Apoptosis). Certain drugs act in specific phase of the cell cycle while others are phase nonspecific.

Question 6

Cell Cycle is divided into 4 phases, list them.

Answer 6

Cell Cycle is divided into 4 phases: G1, S, G2 and M

Question 7

G0: Postmitotic cells exit the cell cycle and enter into a ______ phase e.g., terminally differentiated nerve cells. G0 cells wait for signals to become activated and then resume the cell cycle.

Answer 7

G0: Postmitotic cells exit the cell cycle and enter into a non-proliferative phase e.g., terminally differentiated nerve cells. G0 cells wait for signals to become activated and then resume the cell cycle.

Question 8

S phase = ______ phase & genome is duplicated.

Answer 8

S phase = DNA synthesis phase & genome is duplicated (i.e., 2x).

Question 9

Two Major Proteins Control Cell Cycle Progression:

______: the regulatory proteins

______: the catalytic proteins

Answer 9

Two Major Proteins Control Cell Cycle Progression:

Cyclins: the regulatory proteins e.g., cyclins A, B, D or E.

Cyclin-dependent kinases (Cdks): the catalytic proteins e.g., Cdks 1, 2, 4 or 6.

Question 10

Cyclin+Cdk function as heterodimers that ______ target proteins.

Cdks ______ kinase activity unless associated with a cyclin.

______ determines which proteins to be phosphorylated by the cyclin-Cdk complex.

Answer 10

Cyclin+Cdk function as heterodimers that phosphorylate target proteins.

Cdks no kinase activity unless associated with a cyclin.

Cyclin determines which proteins to be phosphorylated by the cyclin-Cdk complex.

Question 11

Hypophosphorylated Rb (retinoblastoma protein) is an important tumor suppressor gene that dissociates from E2F when it is ______ by Cyclin-CDK complexes.

Hypophsophorylated Rb is bound to ______ family of transcription factors. Hyperphosphorylation of Rb results in the release of E2F. E2F activates the transcription of genes whose products control progression from ______ phase.

Answer 11

Hypophosphorylated Rb (retinoblastoma protein) is an important tumor suppressor gene that dissociates from E2F when it is hyperphosphoryated by Cyclin-CDK complexes.

Hypophsophorylated Rb is bound to E2F family of transcription factors. Hyperphosphorylation of Rb results in the release of E2F. E2F activates the transcription of genes whose products control progression from G1 -> S phase.

Question 12

Progression from S phase to G2 phase involves Cyclin ______/Cdk ______ but the targets remain unknown.

Progression from G2 to M involves Cyclin ______/Cdk ______ and there are several target proteins.

Answer 12

Progression from S phase to G2 phase involves Cyclin A/Cdk2 but the targets remain unknown.

Progression from G2 to M involves Cyclin B/Cdk1 and there are several target proteins.

Question 13

Four key cell cycle checkpoints checkpoints:

G1 arrest: if ______ damage, no progression to S

S-phase arrest: if DNA ______ errors no G2

G2 arrest: if DNA ______ no progression to M

M arrest: if improper ______ formation no division

Answer 13

Four key cell cycle checkpoints checkpoints:

G1 arrest: if DNA damage, no progression to S

S-phase arrest: if DNA replication errors no G2

G2 arrest: if DNA damage no progression to M

M arrest: if improper spindle formation no division

Question 14

Hyperactivation of cdks due to cyclin and/or cdk overexpression e.g., Cyclin D ______ in Breast Cancer.

Answer 14

Hyperactivation of cdks due to cyclin and/or cdk overexpression e.g., Cyclin D overexpression in Breast Cancer.

Question 15

Tumors with p53 mutations; ______ of G1 and/or G2

checkpoints. Some anticancer drugs ______ p53.

Answer 15

Tumors with p53 mutations; lack of G1 and/or G2

checkpoints. Some anticancer drugs activate p53.

Question 16

Apoptosis is a physiological process but can be induced by anticancer drugs.

______ in apoptosis:
Dense chromosome condensation occurs along the nuclear periphery. Cell body shrinks although most organelles remain intact.

______ in apoptosis:
Both the nucleus and cytoplasm fragment, forming apoptotic bodies. These are phagocytosed by the surrounding cells.

Answer 16

Apoptosis is a physiological process but can be induced by anticancer drugs.

Early in apoptosis:
Dense chromosome condensation occurs along the nuclear periphery. Cell body shrinks although most organelles remain intact.

Later in apoptosis:
Both the nucleus and cytoplasm fragment, forming apoptotic bodies. These are phagocytosed by the surrounding cells.

Question 17

______ are integral components of apoptotic machinery.

They are ______ proteases and exist as inactive pro-enzymes named pro-caspases. They are activated in response to ______ insults e.g., anticancer drug treatment.

They recognize specific cleavage sites within proteins (including caspases).

Caspases are involved in mediading apoptosis via the Caspase ______. For example, upstream initiator caspases (caspase 8 or 9) cleave and activate downstream effector (executioner) caspases such as 3, 6 and 7.

Answer 17

Caspases are integral components of apoptotic machinery.

They are Cysteine proteases and exist as inactive pro-enzymes named pro-caspases. They are activated in response to apoptotic insults e.g., anticancer drug treatment.

They recognize specific cleavage sites within proteins (including caspases).

Caspases are involved in mediading apoptosis via the Caspase Cascade. For example, upstream initiator caspases (caspase 8 or 9) cleave and activate downstream effector (executioner) caspases such as 3, 6 and 7.

Question 18

The two major apoptotic pathways responsible for activation of caspase cascade: 1) ______ Receptor-dependent Pathway & 2) ______ Pathway (cytochrome ______).

Answer 18

The two major apoptotic pathways responsible for activation of caspase cascade: 1) death Receptor-dependent Pathway & 2) Mitochondrial Pathway (cytochrome c).

Question 19

Intrinsic anticancer drug resistance:

Dysregulation of one or both apoptotic pathways due to:
______ of apoptosis promoting genes/proteins (mutations, deletions or epigenetic mechanisms).

______ of survival or anti-apoptotic genes/proteins.

______ Factors: poor absorption, rapid metabolism or excretion of drugs: low serum levels. Delivery failure e.g., bulky tumors or high molecular mass of drugs such as monoclonal antibodies.

Answer 19

Intrinsic anticancer drug resistance:

Dysregulation of one or both apoptotic pathways due to:
inactivation of apoptosis promoting genes/proteins (mutations, deletions or epigenetic mechanisms).

Hyperactivity of survival or anti-apoptotic genes/proteins.

Host Factors: poor absorption, rapid metabolism or excretion of drugs: low serum levels. Delivery failure e.g., bulky tumors or high molecular mass of drugs such as monoclonal antibodies.

Question 20

Acquired anticancer drug resistance (1):

Acquired drug resistance due to dysregulation of one or both apoptotic pathways during chemotherapy

Many anticancer drugs induce DNA ______. During the course of chemotherapy, many cancer cells acquire the ability to rapidly and efficiently ______ DNA damage. This reduces apoptosis.

Gene ______: amplification of genes triggering overproduction of proteins that make anticancer drugs ______ (e.g., DHFR amplification gives methotrexate resistance).

Increased expression of energy-dependent efflux ______ that ______ drugs out of cells. Transporters of the ATP-binding cassette (ABC) family e.g.,

Answer 20

Acquired anticancer drug resistance (1):

Acquired drug resistance due to dysregulation of one or both apoptotic pathways during chemotherapy

Many anticancer drugs induce DNA damage. During the course of chemotherapy, many cancer cells acquire the ability to rapidly and efficiently repair DNA damage. This reduces apoptosis.

Gene amplification: amplification of genes triggering overproduction of proteins that make anticancer drugs ineffective (e.g., DHFR amplification gives methotrexate resistance).

Increased expression of energy-dependent efflux pumps that eject drugs out of cells. Transporters of the ATP-binding cassette (ABC) family e.g.,

Question 21

Acquired anticancer drug resistance (2):

Decreased drug ______ because the protein molecules that facilitate drug transport inside the cells ______ working. Cisplatin resistance due to multiple mechanisms; one may involve alterations in membrane proteins that facilitate its transport inside cells.

Dysregulation in drug metabolism: some drugs are normally metabolized into active metabolites inside the cells but cancer cells can acquire mechanisms to block drug ______. Some cancer cells with deficiency in Deoxycitidine ______ are resistance to AraC (AKA Cytarabine).

Acquisition of mechanisms by cancer cells to ______ drugs. Some cancer cells overexpress ______ deaminase this gives resistance to AraC.

Answer 21

Acquired anticancer drug resistance (2):

Decreased drug uptake because the protein molecules that facilitate drug transport inside the cells stop working. Cisplatin resistance due to multiple mechanisms; one may involve alterations in membrane proteins that facilitate its transport inside cells.

Dysregulation in drug metabolism: some drugs are normally metabolized into active metabolites inside the cells but cancer cells can acquire mechanisms to block drug activation. Some cancer cells with deficiency in Deoxycitidine kinase are resistance to AraC (AKA Cytarabine).

Acquisition of mechanisms by cancer cells to inactivate drugs. Some cancer cells overexpress cytidine deaminase this gives resistance to AraC.

Question 22

Anticancer Drug Toxicities can be ______ or ______.

Answer 22

Anticancer Drug Toxicities can be Acute or Delayed.

Question 23

Acute anticancer toxicities:

Most anticancer drugs affect ______ dividing normal and malignant cells. This is why sites of acute toxicities include Bone Marrow, Intestinal Epithelium etc.

Toxic Effect on ______ System: Bone Marrow Suppression, Suppression of all blood elements can occur, Myelosuppression—leuko ______, G-CSF (granulocyte colony-stimulating factor) is now given to shorten the period of Leuko ______.

Toxic Effect on Dividing ______ Cells: Oral Mucosal Ulceration, Intestinal Denudation (degridation).

Toxic Effect on Hair Follicles (rapidly proliferating) = ______

Toxic Effect on Reproductive System: Permanent ______ (females), ______ or no sperm (males).

Answer 23

Acute anticancer toxicities:

Most anticancer drugs affect rapidly dividing normal and malignant cells. This is why sites of acute toxicities include Bone Marrow, Intestinal Epithelium etc.

Toxic Effect on Hematopoietic System: Bone Marrow Suppression, Suppression of all blood elements can occur, Myelosuppression—leukopenia, G-CSF (granulocyte colony-stimulating factor) is now given to shorten the period of Leukopenia.

Toxic Effect on Dividing Mucosal Cells: Oral Mucosal Ulceration, Intestinal Denudation (degridation).

Toxic Effect on Hair Follicles (rapidly proliferating) = Alopecia

Toxic Effect on Reproductive System: Permanent Amenorrhea (females), Azoospermia or no sperm (males).

Question 24

Delayed anticancer toxicities:

______ damage (Heart, Lungs, Kidneys or Liver).

Secondary Neoplasia: most ______ agents are Leukemogenic (leukemia promoting).

Some drugs have specific acute effect on major organs:

Cyclophosphamide releases ______ and ______ metabolite that causes Hemorrhagic Cystitis (bloody urine).

Anthracycline Antibiotics such as Doxorubicin cause dose-related ______ Toxicity; therefore we give Dexrazoxane, a ______ agent.

Answer 24

Delayed anticancer toxicities:

Organ damage (Heart, Lungs, Kidneys or Liver).

Secondary Neoplasia: most Alkylating agents are Leukemogenic (leukemia promoting).

Some drugs have specific acute effect on major organs:

Cyclophosphamide releases Nephrotoxic and Urotoxic metabolite that causes Hemorrhagic Cystitis (bloody urine).

Anthracycline Antibiotics such as Doxorubicin cause dose-related Cardiac Toxicity; therefore we give Dexrazoxane, a cardioprotective agent.