Antineoplastics I and II Flashcards
Fluorouracil
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
What type of drug is
imantinib/gleevec
small molecule
What type of drug is fluorouracil
pyrimidine analogue
Lots of rings
lipophilic. will cross membranes.
What type of drug is
6-mercaptopurine
Purine analogue
imantinib/gleevec
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
What type of drug is paclitaxel
taxanes
mitotic inhibitors
Methotrexate
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.
Cyclophosphamide
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.
In nitrogen mustards (cyclophosphamide) the chlorine is…
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
Vincristine/ vinblastine
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
The “classical” antineoplastic drugs induce apoptosis by:
Directly or indirectly inhibiting nucleic acid synthesis and function
inhibiting mitotic spindle function
inhibiting hormone action
miscellaneous mechanisms
“New” antineoplastics- TKinase Inhibitors Inatinib (Gleevec) for CML
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?
Imatinib
Gleevec
A B and C
What type of drugs are cisplatin and carboplatin
heavy metals
Hormone therapties
Estrogen, antiestrogen, androgen
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.
paclitaxel
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.
Cisplatin. carboplatin
Platiunum analogs. Cross linker. Only cis is active. xchanges Cl group for electrons in O, N, P, in DNA
carboplatin - myelosupression
Topoisomerase inhibitors
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
Alkylating agents (ex cyclophosphamide) are more toxic to…
dividing cells. Because dividing cells have a harder time repairing their DNA if there is damage and are thus more apoptotic.
What type of drug is
Bevacizumab/ avastin
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.
What type of drig is
cyclophosphamide
Alkylating agent
Cytotoxic antibiotics
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
Human Haemotopoetic Lineage
Philidelphia Chromosome
t (9,22) activating ABL Tyrosine Kniase
ABL is constituatively activted
Most CML
Some ALL, AML
Retinoic acid
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
Trustuzumab/ herceptin
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.
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
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
Charged drugs
kidney will take care of it
The “new” antineoplastics induce apoptosis by acting as
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
What type of drugs are
vincristine/vinblastine
Vinca alkaloids
mitotic inhibitors
Colections of all of the human kinases
The human kinome (518 members)
What type of drug is
methotrexate
folic acid antagonist
6-mercaptopurine
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
Imatinib (Gleevic) Mechanism/ Toxicity
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
lots of rings
liver will deal with it
What type of drug is
trastuzumab/herceptin
monoclonal antibody
