Pharmacology 3620 Lecture Notes - Lecture 12: Bone Marrow Suppression, Rheumatoid Arthritis, Antimetabolite
1 May 2018
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Department
Course
Professor
Lecture 012: Cancer Chemotherapy II
Objectives
● Name examples of antimetabolite anti-cancer drugs
● Describe how antimetabolite drugs work, their uses and limitations
● Name examples of alkylating agents used for cancer chemotherapy
● Define the basic mechanisms of action of alkylating agents
● Describe the limitations of alkylating agents
Antimetabolites:
● Cell-cycle specific (mainly S-phase)
● Methotrexate
● 6-Mercaptopurine
● Cytarabine (araC)
○ Fludarabine, 2-chlorodeoxyadenosine,
● 5-Fluorouracil
All drugs cause:
● Bone marrow suppression
● Vomiting
● Nausea
1. Methotrexate
● Poor GI absorption
● Distribution: Not in CNS
● Metabolized in liver to polyglutamates and 7-OH-MTX
○ MTX-polyglutamates are trapped inside cells and are toxic
○ 7-OH-MTX can cause crystalluria
● Excretion: via kidneys
● Toxicity
○ Causes bone-marrow suppression
○ Pregnant woman
■ Drugs cause mutations and cross the plenca
○ Skin effects
○ Renal damage
○ Encephalopathy
● Used in combination of many types of cancers
○ Lymphomas, carcinomas, breast cancer
● Has an affinity to immune cells (activity blood cells)
○ Also used to treat autoimmune inflammatory disorders
■ Kill leukocytes that are attack the host
● Psoriasis, rheumatoid arthritis, crohn’s
■ Given at very low doses
● Leucovorin
find more resources at oneclass.com
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○ administered 24 hr after the methotrexate
○ Rescue from MTX toxicity (reduces methotrexate)
2. 6-Mercaptopurine
● Interfere with DNA synthesis
● converted into TIMP by
HGPRTase
○ TIMP is a
hypoxanthine
analogue
○ used for synthesis of
AMP
■ Inhibition of
purine
synthesis
● Pharmacokinetics of 6-MP
○ Poor oral absorption
○ Broad distribution
(except CNS)
○ First pass metabolism (liver)
○ Metabolized to 6-methyl-MP by TMPT or thiouric acid (by xanthine oxidase)
○ Excreted mainly by the kidney
● Mechanism of Action
○ taken up by cell and enters the cytoplasm
○ 1. Converted into TIMP by enzymes
■ Phosphorylated
■ into analogs that are similar to a nucleotide
■ then interfere with DNA synthesis and cause cytotoxicity
■ this is the therapeutic (useful) pathway
○ 2. Converted into thiouric acid by xanthine oxidase
■ Toxic but not to the tumor
■ Can’t treat the tumor!!
○ 3. TIMP and TGMP can be methylated by TPMT
■ (converted to 6-methyl-MP
■ methylated substrates are not cytotoxic
■ also a DETOXIFIED pathway
■ will not contribute to drug effect
● TPMT is highly polymorphic
○ non-identical forms of the enzyme
■ Often have different activity
■ Have a few differences in the DNA sequence leading to changes in the
amino acid sequence
■ Exists in the population at a frequency greater than 5% (less is a
mutation)
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Describe how antimetabolite drugs work, their uses and limitations. Name examples of alkylating agents used for cancer chemotherapy. Define the basic mechanisms of action of alkylating agents. Metabolized in liver to polyglutamates and 7-oh-mtx. Mtx-polyglutamates are trapped inside cells and are toxic. Drugs cause mutations and cross the plenca. Used in combination of many types of cancers. Has an affinity to immune cells (activity blood cells) Also used to treat autoimmune inflammatory disorders. Kill leukocytes that are attack the host. Rescue from mtx toxicity (reduces methotrexate: 6-mercaptopurine. Metabolized to 6-methyl-mp by tmpt or thiouric acid (by xanthine oxidase) Mechanism of action taken up by cell and enters the cytoplasm. Phosphorylated into analogs that are similar to a nucleotide then interfere with dna synthesis and cause cytotoxicity this is the therapeutic (useful) pathway. Timp and tgmp can be methylated by tpmt (converted to 6-methyl-mp. Have a few differences in the dna sequence leading to changes in the amino acid sequence.
