Flashcards in Immunomodulators and Anti-Neoplastics Deck (58):
T/F Cancer is the second leading cause of mortality in the Philippines.
2 Vascular diseases
pRB (retinoblastoma protein) blocks ___
p53 detects ___
pRB blocks E2F
p53 detects DNA damage
pRB control occurs at which phase? How?
S (DNA synthesis) phase
(pRB binds and inhibits transcription factors of the E2F family)
What is "The Last Gatekeeper?" Function? It is involved in what percent of cancers?
P53 - detects DNA damage
P53 - 2 possible responses to DNA damage
1. Acts as a transcription factor (p21 expression activated -> CDK/G1 cyclin inhibited -> DNA repair)
2. Triggers Apoptosis (if damage is irreparable)
"Executioner" proteins that break down the cell
Receptor tyrosine kinases can activate ___
ras ("molecular switch") - for cell proliferation
CCSA vs CCNSA - effectiveness
CCSA - for high growth fraction malignancies (e.g. hematologic cancers)
CCNSA - for both high and low growth fractions (e.g. solid tumors)
Classifications of classical cancer chemotherapeutic agents (3)
1. Chemical structure and resource
2. Cycle or phase specificity
3. Biochem mechanisms
2 kinds of CCNS
Alkylating agents (nitrogen mustards, alkyl sulfonates, ethylenimines, nitrosoureas, platinum analogs)
Main lethal effect of alkylating agents
What else can it target?
Alkylation of DNA at N7 position of guanine
N1, N3 adenine
Alkylating agents undergoes intramolecular cyclization, forming what?
Then targets a nucleophilic cell component directly or through formation of carbonium ions, which targets what?
Nucleophilic grps such as -NH2, -OH, and -SH
Most important consequence of intra- or inter-strand linking
S phase replication block -> G2 block -> apoptosis
Most widely-used alkylating agent
Nitrogen mustards (5)
Streptozocin, carmustine (BCNU), lomustine
*may cause what?
Granulocyte series (for chronic myelogenous leukemia)
Less likely than other alkylating agents to cause leukemia later
Which of these is acutely toxic
Platinum analogs - cisplatin, carboplatin, oxaliplatin
One of the side effects of cyclophosphamide is hemorrhagic cystitis, due to acrolein toxicity. This can be ameliorated by the use of what adjuvant?
Mesna - detoxifies acrolein
Activation of nitrosoureas produces (2)
a DNA-alkylating grp and a protein-alkylating grp
*alkylated proteins produce toxicity
Cl- dissociates, reacts with H2O, causing what?
Carboplatin has fewer side effects but
Intrastrand cross-linking, eventual DNA denaturation
CCSA: Anti-metabolites kill cells in what phase?
Folic acid is essential for the synthesis of (2)
Purines and thymidylates
* folate -> (F(glu)n) -> FH2 -> FH4
*FH4 - methyl grp donor to deoxyuridine (dUMP -> dTMP), also regenerating FH2
Dihydrofolate reductase (DHFR) (higher affinity than FH2)
*interrupts synthesis of thymidylate, purine nucleotides, serine, methionine
Depletion of FH4 causes?
Depletion of dTMP -> "thymineless death"; inhibition of DNA synthesis
Effects of MTX can be reversed by
*Competitive inhibitor or covalently binds to thymidylate synthetase
"Fraudulent" nucleotide (FdUMP)
A prodrug converted to 5-FU in the liver
araC (cytosine arabinoside) analog with fewer side effects
First of the thiopurine analogs found to be effective in cancer therapy
6-MP, 6-TG are metabolized by?
What purine analog has a MOA similar to araC?
(-> triphophate, inhibits DNA polymerase)
Purine analog that inhibits adenosine deaminase, catalyzes adenosine to inosine
Most cytotoxic antibiotics are CCNS, except
4 major mechanisms of cytotoxic action
Which of these is the established cause of cardiotoxicity and associated side effects?
1. Inhibition of topoisomerase II
2. High-aff binding to DNA through intercalation (-> block DNA, RNA synth; DNA strand scission)
3. Binding to cellular membranes (alter fluidity, ion transport)
4. Generation of semiquinone free radicals & oxygen free radicals -- cause of side effects
Anthracycline main MOA (2)
Structurally related molecules?
Intercalation, topo II inhibition
Mitozantrone (doxorubicin, daunorubicin, epirubicin, idarubicin)
Intercalates in DNA minor groove between adjacent GC's; interfere w RNA pol
Chelates Fe; generation of superoxide and/or hydroxyl radicals
Bleomycin (glycopeptide antibiotic)
Little myelosuppression BUT causes pulmonary fibrosis
Examples of mitotic inhibitors (4)
These induce effect on what?
Vinca alkaloids (vincristine - childhood acute leukemia)
Vincristine vs vinblastin
Paresthesia, muscle weakness
More potent myelosup
Topoismoerase inhibitors arrest cell cycle at what phase?
Topo I - camptothecins
Topo II - podophyllotoxin derivatives (can inc risk of 2nd cancer, AML)
Glucocorticoids used against?
Estrogen (e.g. fosfestrol) recruit cells in...
G0 -> G1; better targets for cytotoxic drugs (haha di ko 'to gets??)
Progestogens (e.g. megestrol, medroxyprogesterone) used for?
Endometrial, renal tumors
How do GnRH analogs (goserelin) work?
Inhibit gonadotropin release (duh huhu) -> dec circulating estrogens
Flutamide, cyproterone for
Prostate tumors (androgen antagonists)
Trilostane, aminoglutethimide inhibit?
Sex hormone synthesis
Protein Kinase inhibitors (imatinib mesylate) for?
CML (chronic myeloid leukemia), GIST (gastrointestinal stromal tumors)
(inhibit transduction signals transmission)
Monoclonal Ab against EGFR
Metastatic colorectal, head and neck CA
Monoclonal Ab for lymphoma therapy
Monoclonal Ab indicated in HER2 Neu positive breast CA therapy
*HER2 structurally similar to EGFR)
Small inhibitor of kinase; inhibits PDGF activity and Bcr/Abl kinase (which is unique to?); also used against NSCLC
Imatinib (Gleevec, Glivec)
Unique to CML
Similar to imatinib
Adverse effects of prototype antineoplastic agents:
Vincristine - cranial nerve palsies
Cisplatin - ototoxicity/tinnitus (C = ears)
Bleomycin, busulfan - pulmonary fibrosis (2B's = lungs)
Doxorubucin (Adriamycin) - heart ("A")
6-thioguanine, 6-mercaptopurine - liver/GI (6-TG - hepatotox; 6-MP - hepatitis, biliary stasis)
Cyclophosphamide - hemorrhagic cystitis (bladder)
Counteracts MTX toxicity
Solution for relapse and met
Targeted therapy - kill most cancer cells
Systemic - wipe out other cells
Effect of location of cancer (brain, liver, CNS)
Brain - drug can't cross BBB
Liver - difficulty going to actual tumor
CNS - intrathecal, need very high doses