2: Lecture 8 Flashcards
Top cases for cancer in each gender
Women: breast cancer, lung and bronchus, and colorectal cancer
Men: Prostate, lung and bronchus, and colorectal cancer
Top deadly cancers in each gender
Women: Lung and Bronchus, breast, and colorectal
Men: Lung and bronchus, colorectal, and prostate
What is a neoplasm
Abnormal growth of tissue that can be benign or malignant
Usually from mutation in control of cell growth leading normal cells to proliferate uncontrollably
Possibilities of a neoplasm
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
Oncogenes and their consequence
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
Oncogene vs Proto-oncogene
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
Drug regimens for cancer cells
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
Cytotoxic agents used for cancer treatment
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
Main action of Antimetabolites
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
Mechanism of Methotrexate (MTX) (antimetabolite)
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
Mechanism of 5-flurouracil (5-FU) (antimetabolite)
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
Combinations for cancer treatments
Methotrexate and 5-fluorouracil as they inhibits different parts of thymidine synthesis, also Leucovorin which potentiates affects of 5-FU (stabilizes binding affinity)
Mechanism of Cytarabine (Ara-C) (antimetabolite)
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
Potential Resistance to Cytarabine (Ara-C)
High cytidine deaminase activity and low dCK activity inactivates the drug (Ara-C)
Mechanism of Gemcitabine (antimetabolite)
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)
Function of alkylating agents
Bifunction to allow formation of covalent links between adjacent bases or between bases of different polynucleotide strands
Examples of Nitrogen mustards (alkylating agents)
Melphalan, Mechlorethamine, and cyclophosphamide
Nitrogen in middle surrounded by chloroethyl groups
Mechanism of Cyclophosphamide (alkylating agent)
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)
Main action of Platins
ex. cisplatin, carboplatin, oxaliplatin
Modify DNA by forming covalent bond between platinum and base to cause crosslinking
Do NOT have chloroethyl groups
What determines cell’s susceptibility to Platins
ex. cisplatin, carboplatin, oxaliplatin
Presence/absence of transporters (CTR1, platins can also enter through passive diffusion)
Resistance mechanism–>downregulate transporters
Influence by BRCA1
What are antitumor antibiotics?
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
What is Topoisomerase II
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
Mechanism of Daunorubicin and doxorubicin
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
Main action of Etoposide (plant alkaloid)
Stabilizes topoisomerase II-DNA cleavable complex
Same mechanism as Doxorubicin
