Mar23 M3-Principles of Management of Cancer of Blood Flashcards
goal of cancer therapy + one example of targetted process
- take advantage of what’s different in cancer cells
- cells proliferating is one thing different
solid tumor vs blood (liquid) tumors preferred modalities of treatment
solid = surgery and radiation liquid = chemotherapy and host immunodefense (stimulate the immune system)
4 chemotherapeutic drug types
- DNA alkylating
- anti-metabolites
- anti-microtubules (natural products)
- topoisomerase inhibitors (natural products)
examples of specific targets of chemotherapy
- steroid hormone Rs (with prednisone, a glucocorticoid)
- enzymes involved in signaling (tyrosine kinase inhibitors (imatinib))
- cell surface molecules (target with Abs like rituximab (anti-CD20), brentuximab (anti-CD30), pembrolizumab (anti-PD1)
4 phases of the cell cycle in order + main checkpoints
G1, (checkpoint), S, G2, (checkpoint), M, (checkpoint), G0 or G1 again
S-phase specific chemotherapy drugs and some examples
- anti-metabolites*
1. S phase specific and SELF LIMITING - methotrexate
- 5-fluorouracil
2. S phase specific - cytosine arabinoside, also called cytarabine, (a nucleotide analog. blocking transformation of oxynts to deoxynts
- hydroxyurea
- topoisomerase inhibitors* (block S-G2 phase)
- daunorubicin
M-phase specific chemotherapy drugs and some examples
microtubules blocking
- vincristine
- vinblastine
- taxols
non cell cycle specific chemo drugs and some examples
DNA alkylating and damaging drugs
- cyclophosphamide
- dicarbazine
cyclophosphamide active portion
- looks like adenine, can bind guanine on position N7
- active part is N with 2 CH2CH2Cl branches
- 1 molecule of the drug binds with other molecule that is next to it on other DNA strand (cross
cyclophosphamide mechanism of action
- 1 molecule of the drug binds with other molecule that is next to it on other DNA strand (cross-linking)
- cross-linking is hard to repair. get mispairing mutations that have to be repaired.
dacarbazine mechanism of action (other alkylating agent)
- methylates guanine at O-6 and N-7 positions
- causes mispairing because it modifies guanine
- DNA damage kills the cell
problem of alkylating agents as chemo drugs
- toxicity to rapidly proliferating cells (BM, GIT, gonads)
- resistance to them (increased inactivation by nucleophilic trapping agents, increased DNA repair, decreased activation)
normal thymidine (TMP) formation cycle in the cell
- dihydrofolate is made into tetrahydrofolate by dihydrofolate reductase
- methylation reaction by thymidylate synthase to synthesize TMP
methotrexate (anti-metabolite, acts on S phase) mechanism of action
- inhibits dihydrofolate reductase (acts on normal folic acid biochem)
- methotrexate polyglutamates inhibit thymidylate synthase
- *no TMP made, building block of DNA, can’t make DNA**
ways cancer cells develop resistance to methotrexate
- inhibit active transport
- inhibit polyglutamate
- change dihydrofolate reductase
- amplify dihydrofolate reductase (more genes for it)
5-fluorouracil (anti-metabolite, S phase specific) mechanism of action
- transfers fluorine on thymine to replace its methyl group*
- inhibition of RNA processing
- incorporation into DNA
cytarabine (also called cytosine arabinoside) (anti-metabolite, S phase specific) mechanism of action
- modifies sugar (deoxyribose) on nts.
- competes with dCTP (cytosineTP) and induces strand breaks and triggers apoptosis
vincristine and vinblastine (vinca alkaloids) mechanism of action
- bind mtb monomers (tubulin)
- terminate assembly of mtbs causing depolymerization and mitotic arrest
- bad chromosome segregation: cell dies
taxols mechanism of action
promote microtubule assembly and inhibit their disassembly (necessary for chromosome segregation)
daunorubicin (doxorubicin) (topoisomerase inhibitor) mechanism of action
- intercalates in DNA
- inhibits topoisomerase II causing DNA strand breaks (this enzyme normally repairs DNA)
topoisomerase inhibitors (block cell cycle at S-G2) structure of the molecule + used in what conditions
- tetracycline, flat ring structure
- in some leukemias (AML, ALL, CML)
bleomycin what kind of drug + mechanism of action
- DNA damaging drug*
- binds DNA, Fe and forms radicals
- consequence = single and double strand breaks + chromosomal aberrations
prednisone mechanism of action (in the more specific drugs) + used more in what cancers
- glucocorticoid receptor agonist
- in response to this TF, many genes are expressed, and are involved in immune response
- blood cancers, breast cancers (act on estrogen R activation), prostate cancer (act on androgen R activation)
most discussed example of translocation in leukemia
chronic myelocytic leukemia. translocation of Abl on chrom 9 and Bcr on chrom 22. forming philadelphia chrom with both on it
behavior of the bcr-abl fused protein
- tyrosine kinase that is always active (bc abl had a kinase domain that can phosphorylate stuff)
- constantly activating GRB-2, SHC, etc. and promoting proliferation
drug used in CML (M for myelocytic or myelogenous or myeloid) and also in ALL (acute lymphoblastic leukemia)
imatinib (Ab to the kinase domain of the bcr-abl fusion protein). bcr-abl stops phosph. everything all the time
*cells don’t die but stop proliferating
rituximab mechanism of action and used in what cancers
- destroys both normal and malignant B cells (bc binds CD20)
- complement mediator cytotoxicity 2. engulfing by macrophages bc of Ab recognition 3. direct lysis by NK cells
- used in CD20+ NHLs (non Hodgkin lymphomas)
brentuximab vedotin mechanism of action
- drug delivery Ab (NOT for targeting by macrophages)
- a CD30 Ab conjugated to a potent anti-mtb agent by a linker that can be cleaved by proteases
- Ab binds CD30, complex engulfed by the cell, proteases cleave the complex, mtb drug cleaves mtbs
brentuximab used in what conditions
Hodgkin lymphomas with CD30+ cells
normal T cell-tumour cell interaction and how this leads to the tumor cell not being killed
- receptor on T cell recognizes a surface molecule on tumor cell
- PD-1 R on T cell interacts with PD-1 ligand (PD-L1) on tumor cells, which tells the T cell not to kill the tumor cell
pembrolizumab mechanism of action
- Ab that binds PD-1 on T cells
- PD-1 and PD-L1 (on tumor cells) interaction can’t occur
- tumor cell will get killed
3 principles of classical cancer chemo
- cure means death of every malignant cell
- you can’t rely on host mechanisms to eliminate a moderate nbr of cancer cells
- cell-kill follows first order kinetics (a constant % of cells are killed)
principles of chemo drugs administration (what kind of strategy is usually used)
- high dose
- intermittent (give drug, wait, give drug, wait)
- drug combinations
special strategy of chemotherapy used in some cancers like prostate cancer
take out patient cells, do chemo, put cells back (idea to help immune system recognize that cancer cells are foreign)
consequence each time you give a chemo treatment
patient gets weaker and sicker (each treatment has its adverse effects)
how chemo drugs are selected (5)
- efficacy
- toxicity
- optimum scheduling
- mechanism of interaction
- avoidance of arbitrary dose changes
- synergistic toxicity has to be only to tumor cells, not normal cells
why combination chemotherapy is what is done usually
- max cell killing with tolerable toxicity
- broader range of drug-tumor interactions
- prevents slow development of resistance
chemo combination usually used in ALL
- vincristine (blocks mtb assembly)
- prednisone (glucocort R agonist)
- doxorubicin or daunorubicin (also called adriamycin) (intercalating agent + topoisomerase II inhibitor)
chemo in CML
imatinib (tyrosine kinase bcr-abl inhibitor)
chemo combination in Hogkin lymphoma
ABVD
- adriamycin (doxorubicin) (intercalating agent + topoisomerase II inhibitor)
- bleomycin (DNA damaging)
- vinblastine (blocks mtb assembly)
- dacarbazine (alkylating agent, modifies guanine, causing mispairing and cell death)
chemo used in non Hodgkin lymphoma
CHOP
- cyclophosphamide (alkylating agent, 2 CH2CH2Cl cross-linking. cytotoxic)
- doxorubicin (H)
- vincristine (O)
- prednisone (P)
