Pharm II (chemo 1b)
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Pharm II (chemo 1b)
Pharm II chemo 1b
Pharm II (chemo 1b)
What are some Alkylator Toxicities?
1. Bone marrrow suppression
2. Vessican properties
3. Hemorrhagic Cystitis
4. Secondary Malignancies
What are some Unique Toxicities of Alkylators?
- interstial fibrosis
- antabuse effect
What are the 5 key points about Alkylators?
1. alkyl group is reactive
intermediate of all alkylating agents
2. cell cycle non-specific
(sometimes called radiomimetic)
3. most are vesicants
4. broad range of use
particularly H.D., non-hodgkin’s lymphoma, and breast cancer
5. myelosuppression is most common dose-limiting toxicity
What are some Common Properties of Anti- Metabolites?
1. Most active during DNA synthesis
2. Inhibit DNA, RNA, and protein synthesis
3. First family of
What are the Different Families in the Anti-Metabolites?
1. anti-folates eg.
2. pyrimidine analogues eg.
3. purine analogues eg.
4. urea analogues eg.
What is the Mech of Action of Methotrexate?
1.thymidylate synthetase (makes Thymine) requires reduced folate
2. DHFR is an enzyme that is required to convert oxidized folate to reduced folate
is similar to oxidized folate and
competes with oxidized folate for access to DHFR
--> thus inhibiting Thymine production.
Slightly acidic (soluble in Basic enviroments)
Does not Cross the BBB
How is resistance developed against Methotrexate?
The Cancer cells
increased production of DHFR
decreased affinity of DHFR for MTX
decreased drug uptake
What is some toxicity of Methotrexate?
- bone marrow suppression
- skin rashes
- pulmonary toxicity
Where does Methotrexate Accumulate? what is this called?
It collects in
it is slowly released from there mimicking a slow infusion of the drug.
This is called
What is Leucovorin (folic acid) Rescue?
1. cancer cells have higher GF
than non-cancer cell population
2. methotrexate is more activein higher GF cell population
may rescue Normal tissue with lower GF cell population with
excess reduced folate
by increaseing 5-FU toxicity.
4. dangerous and timing is critical
What is the Mech of action of 5-FU?
1. 5-FU converted to (f-dump)
5f-dump competes with dump for Thymidylate Synthase
1. 5F-UMP incorporated into
acts as false pyrimidine
What is special about Flucytosine?
In FUNGAL CELLS It can also be converted to 5f-dump--> inhibiting TS--> inhibiting DNA synthesis.
What are the Cancer cells mech of Resistance to 5-FU?
1. decreased activation of 5-FU
2. increased activity of TS
3. reduced drug sensitivity of enzyme
What can increase the effectiveness of 5-FU?
When do you use 5-FU treatment?
, this creates an additional bond between the 5-fdump and the TS.
Colorectal, Breast and GI cancers
What is the Toxicity of 5-FU?
Skin - (sun sensativity and venous discoloration)
Facts about Capecitabine (Xeloda)
It is a prodruge that is converted to 5-FU in the liver
It mimics the action of 5-FU
Toxicity is HAND AND FOOT SYNDROME
What is ARA-C mechanism of action?
1. incorporated into DNA
2. inhibits DNA polymerase
3. inhibits DNA elongation
What is the Mechanism of Resistance to ARA-C?
1. increased activity of cytidine deaminase (inactivates it)
2. decreased activity of deoxycytidine kinase (activates the drug)
3. decreased affinity of DNA polymerase for ARA-C
When do you used ARA-C?
What is its toxicity?
What is Gemcitabine?
1. cytosine analogue that is structural similarities to ARA-C
2. key drug in treatment of
What are the two Purine Analogues?
6 MP and 6 TG
What are the Purine analogues Mech of action?
They are substrates of HGPRT (enzyme that salvages Purines for later use).
They are converted to False Purines (6 Thio GMP) and (6 Thio IMP)
They are incorportated and inhibite DNA synthesis. Attach the 1st commited step of DNA synthesis
6-MP and 6-TG
1. metabolized to deoxynucleotides and incorporated into DNA.
3. active during DNA synthesis - inhibit it
How is resistance generated aggainst 6-MP and 6-TG?
decreased activity of
When do you use 6-MP and 6-TG?
What are some Toxicities?
- D/ N / V
Decreases activity of 5-FU by inhibiting
which is needed to convert 5-FU to 5-Fdump
- increases activity of purine analogs Because PRPP is needed to incorporate them into DNA
Facts about Hydroxyurea
1. analogue of urea
2. inhibits ribonucleotide reductase that converts RNA to DNA and thus inhibits DNA synthesis.
What Targets DHFR (Converts Ox folate to Red folate)?
What targets TS that makes DNA?
What targets DNA polymerase
What Targets Ribonucleotide reductase?
cell cycle specific
has a unique target
toxicity of - myelosuppression and GI