32 Cytotoxic Drugs Flashcards
Acronym for 5 cytotoxic drug classes
List these
PATAM Platinating drugs Alkylating drugs Topoisomerase poisons Antimetabolites Mitotic poisons
2 general mechanisms of Antimetabolites?
- block ENZYMES required for nucleic acid synthesis = lack DNA synthesis PRECURSORS
- MIMIC nucleic acids/metabolites = INCORPORATED into DNA
What is the final RESULT of antimetabolites
activation of S-phase CHECKPOINT
Give 3 examples of antimetabolites
Ara-C (cytosine analogs)
MTX (methotrexate)
5-FU
How does the Ara-C ENTER cells? What happens after cell entry? What CANCER type is it used for? What is its MoA? What is it INACTIVATED by?
Entry: Nucleotide transporters
Activation by cytidine KINASE to 3P version
LEUKEMIA
- Inhibit DNA synthesis
- Incorporated into DNA
= activate S-phase CHECKPOINT
Inactivated by cytidine DEAMINASE to uridine derivatives
What is a problem that inactivating mechanisms can cause?
Resistance to the drug
What is MTX
Methotrexate
MoA of MTX?
Inhibits DHFR
= inhibits production of tetrahydrofolate
= inhibits dTMP + purine synthesis
= activates S-phase CHECKPOINT
What cancer is MTX used for?
Breast
How does the 5-FU ENTER cells?
What is its MoA?
What is it INACTIVATED by?
Entry: Uracil transporters
- Inhibits TS (thymidylate synthase)
= depletes dTMP - Incorporated into DNA
= activate S-phase CHECKPOINT
Inactivated by DPD
How is DPD inactivation of 5-FU overcome?
LARGE DOSE to saturate DPD
Function of ALKYL drugs
Attach ALKYL groups by reacting with the most EN groups on DNA
Name the 4 types of alkylating drugs
Nitrogen mustard
Cyclophosphamide
TMZ + Dacarbazine
How does Nitrogen mustard ENTER cells?
What is its MoA?
Entry: Choline transporter MoA: 2 chloroethyl groups alkylate at 2 positions = INTER-strand x-link = activates S-phase CHECKPOINT
What is a PRODRUG?
Activated IN cancer cells only
eg. cyclophosphamide
Cyclophosphamide MoA?
Activated by LIVRE p450 enzymes to 4-OH-cyclophosphamide
This exists in EQUILIBRIUM with ALDOphosphamide, which is taken up by cancer cells
Alsophosphamide converted to PHOSPHORAMIDE MUSTARD
= INTER-strand x-link
= activates S-phase checkpoint
Result of INTER-strand checkpoints?
KINK in DNA (distorted)
Formation of DNA repair foci complex
= blocks transcription + translation
What do TMZ and Dacarbazine have in common?
MONO-alkylating agents (methylating)
How are TMZ and Dacarbazine activated?
TMZ - activated SPONTANEOUSLY in plasma
Dacarbazine - must be activated by LIVER
MoA of TMZ and Dacarbazine?
Forms MTIC, which methylates O6Me-G
= mispairs with I
= activates MMR
= activates S-phase CHECKPOINT
What is the “active agent” that actually causes damage from MONO-alkylating agents such as TMZ and Dacarbazine?
MTIC
Name a platinating drug
Cisplatin
How was Cisplatin discovered
Accidentally in an electrophoresis experiment
How does the Cisplatin ENTER cells?
What happens after cell entry?
What is its MoA?
What is it INACTIVATED by?
Entry: Cu transporter
Activated by reacting with water to give AQUATED form
MoA:
Aquated form reacts with PURINES
= INTRA-strand x-links between adjacent purines
= DNA distorted towards MAJOR groove
= activates S-phase CHECKPOINT
What are the 2 aspects of “KNOTTING” of DNA
TWIST - # helical turns of 1 strand around another
WRITHE - supercoiling (# turns of double-helix crosses over itself)
What does TWIST and WRITHE give rise to?
T+W = Linking number (“TENSION”)
Name the 2 types of DNA topoisomerases and their function
Type I - makes SSBs = ∆LN in steps of 1
Type II - makes DSBs = ∆LN in steps of 2
Explain the NORMAL MoA of type I topoisomerases?
- Break 1 DNA strand, joints 3’P end to TYR in active site
2. Rotation + RELIGATION of DNA
Name a type I topoisomerase POISON and its MoA
Camptothecin
Prevents religation, forming a topoI-CPT complex
= activates S-phase checkpoint
Explain the NORMAL MoA of type II topoisomerases?
- Binds BOTH strands of DNA (G/T segments)
- Breaks G-segment, translocates T-segment
- RELIGATES G-segment
= DSB
Name 3 type II topoisomerase POISONS
Doxorubicin
Daunorubicin
Etopiside
How do MITOTIC poisons work?
Binds b-subunit of tubulin
= inhibits MT function (attaching to kinetochores, disrupt spindle apparatus)
= activates MITOTIC CHECKPOINT
= mitotic CATASTROPHE
Give 2 examples of mitotic poisons and their MoA
Vinblastine - binds to POLYMERISING end (inhibits elongation)
Paclitaxel - STABILISES MTs (inhibits SHORTENING)
List some mechanisms of creating SELECTIVITY
Uptake - transporters
Trapping of active form - eg. Ara-C (cytidine kinase)
High [target proein] eg. Topoisomerase poisons
Lacking enzyme inactivating mechanisms eg. MGMT-deficient
SHORTER CC - higher proportion of S-phase cells, suits mitotic poisons
Clinically, how are cytotoxic drugs usually used?
COMBO of 2 or more drugs
