Antineoplastics I and II

Question 1

Fluorouracil

Answer 1

pyramidine analogue

blocks dUMP to dTMP by inhibiting thymidylate synthetase

Must be phosphorylated in the cell. 5FU to 5-FUMP, then reduced to active nucleotide 5-FdUMP. 5-FdUMP then covalently binds to thymidylate synthetase in combination with folate cofactor. 5-FU also incorporated into DNA (as FdUTP, mimicking dTTP) and RNA (as FUTP). 5-FU nucleotides also inhibit RNA processing

leukemia, lymphoma, sarcoma, and solid tumors

Question 2

What type of drug is

imantinib/gleevec

Answer 2

small molecule

Question 3

What type of drug is fluorouracil

Answer 3

pyrimidine analogue

Question 4

Lots of rings

Answer 4

lipophilic. will cross membranes.

Question 5

What type of drug is

6-mercaptopurine

Answer 5

Purine analogue

Question 6

imantinib/gleevec

Answer 6

Small molecule

PH+ tyrosine kinase inhibitor

imantinib inhibits ATP binding of the Arc-Alb tyrosine kinase which is constituatively activated due to t(9;22) in CML (philidelphia chromosome)

BRC/ALB -> RAS/RAF -MEK1/2-MAPK

BRC/ALB ->JAK/STAT

Useful in GIST (GI stromal tumors; imhibits c-KIT, PDGFR, other kinases) also in CML, mylodysplastic diseased, and myeloproliferative diseases

Can become resistant due to

Brc-Alb mutation

Mutation in tyrosine kinase

Increase expression of ABC transporter P170

Question 7

What type of drug is paclitaxel

Answer 7

taxanes

mitotic inhibitors

Question 8

Methotrexate

Answer 8

Folic acid antagonist

Folic acid analog that had affinity for folate reductase. Converts folic acid to dihydrofolic and tetrahydrofolic acid. FH4 is a cofactor for single carbon transfers required for de novo synthesis of thymdine, adenine, guanine, methionine, and glycine. Critical effect is on thymidylate and thymidylate synthetase. Inhibited thymidylate synthetase done through reduced levels of FH4. Also done by occupation of folate cofactor site by methotrezate. Leads to apoptosis. Methotrexate blocks reduction of FH2 to FH4 by dihydrofolate reductase. FH4 is required to turn dUMP to dTMP

Toxic to all dividing cells in the body. Can cause major toxicity. Use leucovorin to rescue normal cells. Used in carcinoma of the breast, head and neck ovary, and bladder.

Inhibits DHFR and thus inhibits one carbon transfers used in de novo purine synthesis and conversion of dUMP to dTMP. DNA synthesis fails and apoptosis is induced.

Question 9

Cyclophosphamide

Answer 9

Alkylating agent.

Came from mustard gas. Prodrug. Activated by CYP450 in liver to become bifunctional carbonic ions (carbocations).

Alkylating agents can covalently attach to N7 of guanine nucleic acid. Can cause mutation (base pair transformation or strand scission with depurination) important that this can act as bifunctional alkylation.They can crosslink DNA strands. Cross linking is more resistant to exccision repair than monoalkylation. Prevents replication and kills the cell

Used widely in solid and hematogenous tumors; congener ifosfamide used for sarcomas and testicular tumors.

Question 10

In nitrogen mustards (cyclophosphamide) the chlorine is…

Answer 10

a good leaving group, thus making a highly reactive carbonium ion.

Note that the carbonium ion is formed so quickly that this drug needs to be given IV at a site near the tumor so that it does not react with noncancerous tussue

Question 11

Vincristine/ vinblastine

Answer 11

vinca alkaloids

mitotic inhibitor/ spindle poison

binds to tubules and disrupt the balancce between microtubule polymerization and depolymerization, causing dissolution of microtubules and metaphase arrest

Used in cells that are synchronized in metaphase

Question 12

The “classical” antineoplastic drugs induce apoptosis by:

Answer 12

Directly or indirectly inhibiting nucleic acid synthesis and function

inhibiting mitotic spindle function

inhibiting hormone action

miscellaneous mechanisms

Question 13

“New” antineoplastics- TKinase Inhibitors Inatinib (Gleevec) for CML

Answer 13

In CML ~20% NR, ~15 become resistant within 8 years

Imatinib, Nilotinib, Dasatinib as primary tx; Bosutinib, Ponatinib as secondary

Useful in GIST (GI stomal tumors; inhibits c-KIT, PDGFR, other kinases)

Use in combination with new/classical agents for molecular response?

Question 14

Imatinib

Answer 14

Gleevec

Question 15

Answer 15

A B and C

Question 16

What type of drugs are cisplatin and carboplatin

Answer 16

heavy metals

Question 17

Hormone therapties

Estrogen, antiestrogen, androgen

Answer 17

Steroid hormones used in treatment of tumors that are HR+ (hormone receptor positive).
Treatment of hormone dependent tumors. Alterations in transcription, cell growth, and division in tumors that have receptors for the hormone. The steroid receptor complex binds to sequence specific sites and act as an “enhancer” to activate distinct transcriptional programs. Used to antagonize steroid-dependent tumor growth.
Use androgen or estrogen antagonist for estrogen dependent tumors and androgen dependent tumors.

Question 18

paclitaxel

Answer 18

taxanes

natural antineoplastic from yew tree. Bind to tubules at a site different from vinca alkaloids. Stabilize microtubules so that they can not disaggregate, producing mitotic arrest.

Resistance can occur in cells that have elevated p-glycoprotein that enhances drug efflux

used in leukemias, breast cancer, melanoma, and ovarian carcinoma. Effective in treating drug resistant breast and ovarian tumors.

Question 19

Cisplatin. carboplatin

Answer 19

Platiunum analogs. Cross linker. Only cis is active. xchanges Cl group for electrons in O, N, P, in DNA

carboplatin - myelosupression

Question 20

Topoisomerase inhibitors

Answer 20

Binds to DNA/topoisomerate II, stabilized cleaved dsDNA and preven strand passage and ligation in supercoil relaxation, resulting in dsDNA breaks.

Used for lymphomas, lung, gastric, and other cancers.

Increased secondary AML

Question 21

Alkylating agents (ex cyclophosphamide) are more toxic to…

Answer 21

dividing cells. Because dividing cells have a harder time repairing their DNA if there is damage and are thus more apoptotic.

Question 22

What type of drug is

Bevacizumab/ avastin

Answer 22

monoclonal antibody acting as angiogenesis inhibitor. RhMAb agains VEGF, reducign vascularization of tumor tissues (prevents angiogenesis).

Useful in AMD, colorectal cancer, diabetic retinopathy

Withdrawn for breast CA

Monoclonal antibody agains VEGF (vascular endothelial growth factor). Prevents angiogenesis. useful in NSCLC (nonsmall cell lung cancer) renal cancers. ALso certain eye dzs like age related macular degeneration.

Question 23

What type of drig is

cyclophosphamide

Answer 23

Alkylating agent

Question 24

Cytotoxic antibiotics

Answer 24

Isolated from streptomyces. Reduce template capacity of DNA for replication and transcription.

Ex: actinomycin D. Drug intercalated (inserts itself) between 2 adjacent guanines. Then generates free radicals that damage DNA. Binding of drug inhibits transcription (RNA synthesis by RNAP I, II, and III) Higher doses also inhibits replication by DNA polymerase

Some intercalate without base specificity. Intercalating drugs also interfere with the ability of topoisomrerase IIto cleave, supercoil, and ligte DNA strands, leading to stand breakage.

Some also function as redox center (with ring) where center accepts electrons from donor molecules and then gives them away and produces superoxide anion radicals. These radicals initiate radical mediated chain reactions that lead to DNA strand breakage

Question 25

Human Haemotopoetic Lineage

Answer 25

Question 26

Philidelphia Chromosome

Answer 26

t (9,22) activating ABL Tyrosine Kniase

ABL is constituatively activted

Most CML

Some ALL, AML

Question 27

Retinoic acid

Answer 27

Alter transcription to trigger genetic programs allowing differentiation of tumor cells. In acute promyelotic leukemia (APL) ther is a translocation t(15;17) that interrupts gene for the retinoic acid receptor aplha (RARalpha). Recall that RA combines with an intracellular receptor which then bins to RA response element (RARE) which regulates myeloid differentiation. In abcense of functional RAR, promyelocytes can not differentiate and thus remain in proliferative promyelotic form.

Mechanism is not completely known but there are several hypotheses

1) RA in high doses stimulates defective RARalpha
2) RA in high doses indices alternative RAR pathway
3) the abberant RARalpha may act as dominant negative mutant suppressing the function of coexpressed nonmal RARalpha allele
4) Release of suppressor molecules from the steroid receptor with elevated RA

Question 28

Trustuzumab/ herceptin

Answer 28

Monoclonal antibody to membrane receptor. RhMAb to transmembrane receptor EGFR subunit Her2. Her2 is overexpressed in some metastatic breast CA and other tumors. Direct antibody agains Her2-neu receptor.

Question 29

Resistance to inatinib could arise by means of

A: Bcr-Abl gene amplification

B: A mutation in Abl tyrosine kinase

C: Induction of the ABC transporter P-170, the product of the MDR-1 gene

D: A and B

E: A, B, and C

Answer 29

A B and C

A- if we amplify gene that is causing problem, we now have inadequate dose

C- endogenous transporter that transports large lipophilic things. pumps drug out

Question 30

Charged drugs

Answer 30

kidney will take care of it

Question 31

The “new” antineoplastics induce apoptosis by acting as

Answer 31

Signal transduction inhibitors of driver mutations, commonly inhibiting tyrosine or serine/threonine kinases

angiogenesis inhibitors

antibodies directed against tumor antigens (neoantigens)

CAR-T cells (chimeric antigen receptor T cells) engineered to express tumor antigen receptors

antibodies serving as “checkpoint inhnitors” that sensitize the immune system to tumor neoantigens

Question 32

What type of drugs are

vincristine/vinblastine

Answer 32

Vinca alkaloids

mitotic inhibitors

Question 33

Colections of all of the human kinases

Answer 33

The human kinome (518 members)

Question 34

What type of drug is

methotrexate

Answer 34

folic acid antagonist

Question 35

6-mercaptopurine

Answer 35

6MP is a prodrug turned into 6MPRP (6-mercaptopurine ribose phosphate) by HGPRT in salvage pathway

Must be turned into nucleotides to be toxic within the DNA

6MPRP is the thioanalogue (T-IMP) of IMP (inosine monophosphate) T-IMP noncompetatively inhibits IMP conversion toadenylosuccinic and xanthylic acids. Thioguanine is synthesized and incorporated into the DNA where it disrupts replication and transcription

Inhibits purine synthesis. Inhibit DNA and RNA synthesis, repair, and fn. Sometimes metabolized by the same enzymes as allopurinol, thus you need to lower your dose of allopurinol. 6MP phosphorylated to 6T-IMP which inhibits enzymes for ATP and GTP synthesis. Then incorporated into DNA where is disrupts structure/fn

Question 36

Imatinib (Gleevic) Mechanism/ Toxicity

Answer 36

Inhibits the ATP binding site on the Bcr-Abl tyrosine kinase which is constituatively activated due to t(9;22) in CML

Complete hematological resp in up to 95% in chronic phase

~75% have a complete cytogenic response

Metabolized by hepatic CYP3A4: caution due to drug interactions with warfarin (+) phenytoin (-) St John’s wort (-) grapefruit juice (+)

N, V, D, sv skin rxns, hepatotoxicity, HTN, myelosupression (anemia, neutropenia, thrombocytopenia) edema, CHF, musculoskeletal pain

Question 37

lots of rings

Answer 37

liver will deal with it

Question 38

What type of drug is

trastuzumab/herceptin

Answer 38

monoclonal antibody