Antineoplastics Flashcards
Explain the biosynthesis pathway of pyramidine and purine synthesis.
Ribonucleotides are made first in a cell which are then converted into deoxyribonucleotides later, precursor for all ribonucleotides is UMP (Uridine Monophosphate).
UMP is phosphorylated to UDP
UDP is converted into dUDP (deoxyuridine monophosphate) by ribonucleotide reducatase.
dUDP is converted to dUMP by a kinase.
dUMP is then converted into dTMP via thymidine synthetase. (deoxythymidine monophosphate) In order to do this a methylated THF is required which is then converted to DHF (it loses 2 hydrogens and a carbon in the process of forming dTMP). dTMP is then used to make Thymidine.
Explain the folate cycle.
- Methylated THF is converted to DHF when donating a carbon for a metabolic process like synthesis of thymidine.
- DHF reductase then converts DHF into THF.
- THF is then methylated.
- This cycle continues on.
Explain the MOA of methotrexate.
Methotrexate is a folate analong, it irreversibly binds to DHF reductase enzyme, as a result no THF is formed and the folate cycle comes to a halt. There is a built up DHF in the cell.
What are the indications of methotrexate other than for cancer treatment?
- Non surgical treatment for ectopic pregnancy during early phase
- Abortion
- It can be used to treat psoriasis and psoriatic arthritis.
- Can be used to treat RA with DMARDS therapy.
- Due to its immunosuppressive effect it is used for IBD, SLE, vasculitis, dermatomyositis
What are the side effects of methotrexate?
- Bone marrow suppression, can lead to pancytopenia
- Folate deficiency, this can cause megaloblastic anemia
- Increased risk for infections
- Pulmonary fibrosis - restrictive lung disease
- Hepatotoxicity by directly damaging hepatocytes
- Alopecia, stomatitis
What is leucovorin used for?
Leucovirin aka folinic acid restores folate levels as it does not require DHF reducatase, furthermore it restores DHF activity by displacing methotrexate from its binding site.It reverses the toxicity caused by methotrexate.
What is the MOA of 5FU?
It is metabolised in our body to fdUMP (5 florodeoxyuridine monophosphate)It is a cytotoxic pyramidine analog, forms a complex with thymidine synthetase (which converts dUMP to dTMP) and THF, inhibiting thymidine synthesis.This leads to a build of dUMP.Other metabolites of 5FU also inhibit other processes such as incorporating into growing RNA strands as 5UTP, it inhibits RNA processing and RNA translation, or can get incorporated into DNA as 5dUMP to inhibit DNA’s function
Side effects of 5FU.
- The most significant complication of 5FU is due to the fact that it significantly damages the rapidly dividing cells of intestinal mucosa leading to exfoliation of these cells and causing severe diarrhea.
- Other side effects are cutaneous complications – photosensitivity, rash and hyperpigmentation, myelosuppression & pancytopenia
- Leucovorin does NOT rescue patient from 5-FU.
MOA of Hydroxyurea.
UMP is a precursor to all nucleotides. It is phosphorylated to UDP. UDP (uridine diphosphate) is the substrate for ribonucleotide reductase – UDP -> dUDP. (dUDP -> dUMP -> dTMP).Hydroxyurea inhibits ribonucleotide reductase, preventing UDP conversion into dUDP.
What is 5FU mainly used for?
Colorectal cancer.
What are some other usesof hydroxyurea?What are its side effects?
- Used in reducing veno-occlusive disease like in sickle cell patients, through a poorly understood mechanism it increases the levels of HbF (fetal hemaglobin)
- Diarrhea, mylosuppression and pancytopenia.
What phase of the cell cycle are methotrexate, 5FU and hydroxyurea effective in?
These are anti metabolites, so effective only during the S phase since this is when DNA synthesis takes place.
Explain the process of synthesis of purines.
Purines consist of ribose, nitrogenous base and a couple phosphates. Synthesis starts with ribose. Precursor to all purines is PRPP (Phosphoribosyl pyrophosphate)
PRPP is converted into IMP (Inosine monophosphate)
IMP is then converted either into AMP or GMP (adenosine monophosphate or guanosine monosphosphate)
MOA of Azathiopurine.
Azathiopurine is converted into 6MP (Mercaptopurine).6MP is activated by HPGRT (Hypoxanthine guanine phosporibosyl transferase). This then blocks synthesis of IMP from PRPP,leading to inhibiton of DNA and RNA synthesis. As a result the cell is arrested in S phase.
What are the indication for Azathiopurine?
- 6MP treats hematologic malignancies (e.g. ALL).
- Can also be used to treat autoimmune inflammatory conditions (e.g. graft rejection, SLE, autoimmune hemolytic anemia, RA [but not as effective as MTX for RA],
- IBD [Crohn’s & UC].
What are the side effects of 6MP?
- Myelosuppression, this can lead to infections and reactivation of latent viruses such as EBV
- Pancreatitis and hepatotoxicity
- 6-MP is inactivated by Thiopurine Methyl-Transferase & Xanthine Oxidase. It inhibits Xanthine Oxidase (just like allopurinol) and this leads to increase levels of purine analogues, including 6-MP -> ↑risk of side effects. Due to this, allopurinol has an ability to reduce the dose of 6MP in chemotherapy, sometimes it has to be reduced as much as 75%.
What is the MOA, indication and side effects of Mycophenolate Mofetil?
- Prevents formation of IMP to GMP, it is an IMP dehydrogenase inhibitor.
- This leads to decreased B and T cell proliferation, decrease in antibodies production.
- Can be used to treat autoimmune conditions (e.g. SLE, solid organtransplant rejection, Myasthenia Gravis, RA)
- CAUTION: May cause GI distress (nausea, diarrhea, cramping), can cause myelosuppression -> infections.
Name theNeolithic Antineoplastics.What is their MOA.
Cladribine, Cytarabine and Gemcitabine.They inhibit alpha and beta DNA polymerase, preventing DNA synthesis and repair, arresting cell in the S phase.
What is the MOA, indication and side effects of Cladribine?
- Cladribine (“Clad” in bear skins) – cytotoxic purine analog. Resistant to purine deaminase (so it won’t get degraded) -> can reach very high intracellular levels (cytotoxic). Inhibits DNA polymerase α & β, preventing DNA synthesis and repair (S-Phase).
- Is the drug of choice for treating Hairy Cell Leukemia (“clad in bear hair”), can also be used for other leukemias/lymphomas.
- Side effects: Myelosuppression.
What is the MOA, indication and side effects of Cytarabine?
- Cytarabine “Saber tooth” – cytotoxic pyrimidine analog. Does NOT affect folate cycle. Instead, it is converted into a triphosphate metabolite that competitively inhibits DNA polymerase α & β -> preventing DNA synthesis and repair (S-Phase).
- Cytarabine is only active in hematologic malignancies* (e.g. AML, NHL).
- CAUTION: myelosuppression
What is the MOA, indication and side effects of Gemcitabine?
- Gemcitabine (“gems inside geode”) – cytotoxic pyrimidine analog. Inhibits DNA polymerase α & β -> preventing DNA synthesis and repair (S-Phase). Active against both hematologic malignancies and solid tumors.
- CAUTION: myelosuppression