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
- - procarbazine
- - 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 rationally designed
- chemotherapy agents
What are the Different Families in the Anti-Metabolites?
- 1. anti-folates eg. Methotrexate
- 2. pyrimidine analogues eg. 5-FU, ARA-C
- 3. purine analogues eg. 6-MP, 5-TG
- 4. urea analogues eg. hydroxyurea
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
- 3. methotrexate is similar to oxidized folate and
- competes with oxidized folate for access to DHFR --> thus inhibiting Thymine production.
- Not metabolized
- Slightly acidic (soluble in Basic enviroments)
- Does not Cross the BBB
How is resistance developed against Methotrexate?
The Cancer cells
- - increased production of DHFR
- (gene amplification)
- - decreased affinity of DHFR for MTX
- - decreased drug uptake (gene amplification)
What is some toxicity of Methotrexate?
- - bone marrow suppression
- - skin rashes
- - mucositis
- - hepatotoxicity
- - pulmonary toxicity
Where does Methotrexate Accumulate? what is this called?
- It collects in pleural effusions and ascitic fluid
- it is slowly released from there mimicking a slow infusion of the drug.
- This is called 3rd spacing
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
- 3. 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?
- PRIMARY ACTION
- 1. 5-FU converted to (f-dump)
- 2. 5f-dump competes with dump for Thymidylate Synthase--> inhibits DNA synthesis
- SECONDARY ACTION
- 1. 5F-UMP incorporated into RNA and 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?
Adding reduced folate, 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?
- 1. severe BM suppression
- 2. GI
- 3. unusual neuro toxicity (Cerebellar dysfunction)
What is Gemcitabine?
1. cytosine analogue that is structural similarities to ARA-C
2. key drug in treatment of pancreatic cancer
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?
- 1. decreased activity of HGPRT
- 2. increased drug degradation
When do you use 6-MP and 6-TG?
What are some Toxicities?
- D/ N / V
What does Allopurinol do?
Decreases activity of 5-FU by inhibiting PRPP 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)?
- - methotrexate
- - pemetrexed
- - raltitrexed
What targets TS that makes DNA?
- - 5-FU
- - capecitabine
- - (pemetrexed)
What targets DNA polymerase
- - ARA-C
- - gemcitabine
- - (fludarabine)
What Targets Ribonucleotide reductase?
- - hydroxyurea
- - (fludarabine)
- cell cycle specific
- has a unique target
- toxicity of - myelosuppression and GI