2: Lecture 8

Question 1

Top cases for cancer in each gender

Answer 1

Women: breast cancer, lung and bronchus, and colorectal cancer
Men: Prostate, lung and bronchus, and colorectal cancer

Question 2

Top deadly cancers in each gender

Answer 2

Women: Lung and Bronchus, breast, and colorectal
Men: Lung and bronchus, colorectal, and prostate

Question 3

What is a neoplasm

Answer 3

Abnormal growth of tissue that can be benign or malignant
Usually from mutation in control of cell growth leading normal cells to proliferate uncontrollably

Question 4

Possibilities of a neoplasm

Answer 4

Benign–>cell divides uncontrollably but does not go beyond tissue of origin (immobile)
Malignant–>neoplasm begins having invasive properties and spread from tissue of origin (mobile)
Metastasis–>neoplasm enters blood stream or lymphatic system to reach distant organs

Question 5

Oncogenes and their consequence

Answer 5

HPV (human papillomavirus–>in 100% cervical cancer and 30% head/neck carcinomas
Oncoproteins E6 and E7 (work together to lead to overgrowth of deregulated cells (uncontrollable growth)
E7–>inhibits retinoblastoma (pRB that regulates cell proliferation)
E6–>blocks apoptosis by inducing p53 degradation

Question 6

Oncogene vs Proto-oncogene

Answer 6

Oncogenes–>product is affected in a way that alters cellular function to promote cancer
Proto-oncogene–>actual gene in our genome that results in normal cellular function under normal circumstances

Question 7

Drug regimens for cancer cells

Answer 7

Use Drugs with
Different mechanisms of resistance –>harder for tumor to recover
Minimal or no overlapping toxicities–>to reduce possibility of life-threatening side effects
Different mechanisms of action–>affect tumor cells at different stages of cell cycle
Synthetic lethal combinations–>knockdown of A AND B killing cancer cell but not normal cell

Question 8

Cytotoxic agents used for cancer treatment

Answer 8

1) Antimetabolites–>inhibit DNA synthesis
2) Alkylating agents and anti-tumor antibiotics–>damage or disrupt DNA structure (may interfere with enzymes like topoisomerases)
3) Plant Alkaloids–>disrupt microtubule dynamics during mitosis

Question 9

Main action of Antimetabolites

Answer 9

ex. Methotrexate (MTX), 5-fluorouracil, Leucovorin, Cytarabine, Gemcitabine
Mimic structures to inhibit enzymes required for folic acid regeneration, pyrimidine or purine synthesis, or DNA or RNA synthesis

Question 10

Mechanism of Methotrexate (MTX) (antimetabolite)

Answer 10

Competitive antagonist that inhibits dihydrofolate reductase (DHFR enzyme) (responsible for reducing dihydrofolate to tetrahydrofolate necessary for thymidine synthesis)
Starves cells of thymidine–>inhibits DNA synthesis
Leucovorin (tetrahydrofolate analog) limits side effects of methotrexate

Question 11

Mechanism of 5-flurouracil (5-FU) (antimetabolite)

Answer 11

Small metabolite that inhibits pyrimidine synthesis–>inhibiting DNA replication
A prodrug
5-FU metabolized to FdUMP (pyrimidine analog)–>FdUMP inhibits thymidylate synthase–>prevents conversion of dUMP to dTMP–>imbalance of dNTP and increase UTP–>DNA damage

Question 12

Combinations for cancer treatments

Answer 12

Methotrexate and 5-fluorouracil as they inhibits different parts of thymidine synthesis, also Leucovorin which potentiates affects of 5-FU (stabilizes binding affinity)

Question 13

Mechanism of Cytarabine (Ara-C) (antimetabolite)

Answer 13

Mimics deoxycytidine
Converted to active cytosine triphosphate (Ara-CTP) by deoxycytidine kinase (dCK) followed by nucleoside diphosphate kinase (NDPK)
Causes chain termination
At high doses Ara-CTP is a competitive inhibitor of DNA polymerase

Question 14

Potential Resistance to Cytarabine (Ara-C)

Answer 14

High cytidine deaminase activity and low dCK activity inactivates the drug (Ara-C)

Question 15

Mechanism of Gemcitabine (antimetabolite)

Answer 15

First phosphorylated by dCK and then by kinases
Has activity in both diphosphate AND triphosphate forms
Gemcitabine-diphosphate–>Inhibits ribonucleotide reductase (RNR) to deplete deoxynucleotide triphosphate (dNTP) pools
Gemcitabine-triphosphate–>Inhibits DNA polymerase or terminates chain elongation once incorporated into DNA (chain terminator)

Question 16

Function of alkylating agents

Answer 16

Bifunction to allow formation of covalent links between adjacent bases or between bases of different polynucleotide strands

Question 17

Examples of Nitrogen mustards (alkylating agents)

Answer 17

Melphalan, Mechlorethamine, and cyclophosphamide
Nitrogen in middle surrounded by chloroethyl groups

Question 18

Mechanism of Cyclophosphamide (alkylating agent)

Answer 18

Gets metabolically activated by CYP450s which add a hydroxyl group
Then breakdown to phosphoramide mustard (bifunctional alkylating agent that is capable of crosslinking DNA) and Acrolein (bind proteins and side effects)

Question 19

Main action of Platins

Answer 19

ex. cisplatin, carboplatin, oxaliplatin
Modify DNA by forming covalent bond between platinum and base to cause crosslinking
Do NOT have chloroethyl groups

Question 20

What determines cell’s susceptibility to Platins

Answer 20

ex. cisplatin, carboplatin, oxaliplatin
Presence/absence of transporters (CTR1, platins can also enter through passive diffusion)
Resistance mechanism–>downregulate transporters
Influence by BRCA1

Question 21

What are antitumor antibiotics?

Answer 21

Substances produced by a microorganism to kill another one
Often used will antibacterial agents
ex. anthracycline antibiotics (cytotoxic antineoplastic agents) isolated from Streptomyces
ex. Daunorubicin and doxorubicin

Question 22

What is Topoisomerase II

Answer 22

Enzyme for DNA replication and chromosome segregation
Catalyzes uncoiling and unlinking of both strands of double-stranded DNA (modifies DNA coiling and intertwining of DNA duplexes)–>creating double-strand breaks

Question 23

Mechanism of Daunorubicin and doxorubicin

Answer 23

Poisoning of DNA topoisomerase II (major cytotoxic activity) by stabilizing covalent topoisomerase II-DNA reaction intermediate–>preventing protein-linked DNA breaks from rejoining–>cell death

Question 24

Main action of Etoposide (plant alkaloid)

Answer 24

Stabilizes topoisomerase II-DNA cleavable complex
Same mechanism as Doxorubicin

Question 25

Main action of Topotecan and SN-38 (active metabolite of Irinotecan) (plant alkaloid)

Answer 25

Bind and stabilizes topoisomerase-I-DNA cleavage complex
Trapped TOP1 cleavage complex interferes with DNA replication and transcription–>cytotoxic
Irinotecan is an injected prodrug (SN-38 cannot be injected directly because it is poorly soluble)

Question 26

Which families of drugs target microtubules

Answer 26

Vinca alkaloids and Taxanes
active in topoisomerase I

Question 27

What is Intrinsic resistance

Answer 27

When some initial cells have resistance mechanism and clonal selection causes proliferation leading to stable resistance

Question 28

What is Acquired resistance

Answer 28

Resistance cells are not present at beginning of treatment, but appear afterwards fur to acquired mutation, clonal selection occurs and causes proliferation leading to stable resistance

Question 29

Main action of Vinca alkaloids (Microtubule-targeted antimitotic drug)

Answer 29

ex. vincristine and vinblastine
Bind microtubule ends and block microtubule polymerization, allowing disassembly
Cells blocked in mitosis

Question 30

Main action of Taxanes and epothilones (microtubule0targeted antimitotic drug)

Answer 30

ex. of Taxanes: paclitaxel (requires premedication with corticosteroid since formulated with surfactant) and docetaxel
ex. of epothilones: ixabepilone (not a plant alkaloid)
Bind interior surface of microtubule and stabilize them in polymerized form (no disassembly)
Cells blocked in Mitosis

Question 31

Main action of Abraxane (microtubule-targeted antimitotic drug)

Answer 31

An albumin bound nanoparticle
Increased efficacy and reduced overall toxicity profile than paclitaxel
BUT higher incidence of transient sensory neurotoxicity