Immunomodulators and Anti-Neoplastics Flashcards
T/F Cancer is the second leading cause of mortality in the Philippines.
F
1 Cardiac
2 Vascular diseases
3 Cancer
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
50%
P53 - 2 possible responses to DNA damage
- Acts as a transcription factor (p21 expression activated -> CDK/G1 cyclin inhibited -> DNA repair)
- Triggers Apoptosis (if damage is irreparable)
“Executioner” proteins that break down the cell
Caspases
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)
- Chemical structure and resource
- Cycle or phase specificity
- Biochem mechanisms
2 kinds of CCNS
Alkylating agents (nitrogen mustards, alkyl sulfonates, ethylenimines, nitrosoureas, platinum analogs)
Antibiotics
Main lethal effect of alkylating agents
What else can it target?
Alkylation of DNA at N7 position of guanine
N1, N3 adenine
N3 cytosine
Alkylating agents undergoes intramolecular cyclization, forming what?
Then targets a nucleophilic cell component directly or through formation of carbonium ions, which targets what?
Ethyleneimonium ions
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
Cyclophosphamide
Nitrogen mustards (5)
Mechlorethamine Chlorambucil Cyclophosphamide Ifosfamide Malphalan
Nitrosoureas (3)
Streptozocin, carmustine (BCNU), lomustine
Alkyl sulfonate
- specificity for?
- may cause what?
Busulfan (oral)
Granulocyte series (for chronic myelogenous leukemia) Pulmonary fibrosis
Less likely than other alkylating agents to cause leukemia later
Which of these is acutely toxic
Platinum analogs - cisplatin, carboplatin, oxaliplatin
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
Cisplatin MOA:
Cl- dissociates, reacts with H2O, causing what?
Carboplatin has fewer side effects but
Intrastrand cross-linking, eventual DNA denaturation
More myelotoxic
CCSA: Anti-metabolites kill cells in what phase?
S 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
MTX inhibits
Dihydrofolate reductase (DHFR) (higher affinity than FH2)
*interrupts synthesis of thymidylate, purine nucleotides, serine, methionine
