Cancer Drugs Flashcards
The alkylating agents exert their effects by
on DNA and
protein synthesis by binding to DNA and preventing theunwinding of the DNA molecule.
- Fluorouracil:
It is used for colon cancer, esophageal cancer, stomach
cancer, pancreatic cancer, breast cancer, and cervical
cancer.
Acts as thymidylatesynthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidylate (dTMP), which is a nucleotide required for DNA replication.
Capecitabine
Inhibit dTMP Synthesis
Cytarabine:
Cytarabine (ara-C) is an arabinose analog of cytosine.
Ara-CTP inhibits DNA polymerase, an enzyme responsible for strand elongation.
• Cytarabine is mainly used in the treatment of acute myeloid leukaemia, acute lymphocytic leukaemia (ALL) and in lymphomas
• The toxicity of cytarabine is dose dependent. The most characteristic toxicity of high-dose ara-C (>1 g/m2 per dose) regimens
Gemcitabine
Gemcitabine is a fluorine-substituted deoxycytidine
analog related structurally to cytarabine.
• Gemcitabine is incorporated into DNA, where it inhibits DNApolymerase activity.
• Compared with cytarabine gemcitabine achieves
intracellular concentrations about 20 times higher than
does ara-C, secondary to increased penetration of cell
membranes, and greater affinity for the activating
enzyme deoxycytidine kinase.
Azacytidine and Decitabine: •
Both of these agents are nucleoside analogs, and act by direct incorporation into DNA and inhibition of DNA
methyltransferase which cause hypomethylation of
DNA.
• Azacitidine, marketed as Vidaza, is used mainly in the
treatment of myelodysplastic syndrome
- 6-Mercaptopurine and 6-Thioguanine:
6-Mercaptopurine (6-MP) is used to treat acute lymphocytic leukemia, Crohn’s disease, and
ulcerative colitis.
• Mercaptopurine (6-MP) competes with the purine derivatives hypoxanthine and guanine
for the enzyme HGPRT and is itself converted to thio inosine monophosphate (TIMP). • TIMP inhibits several chemical reactions
• In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. • Both TIMP and MTIMP have been reported to inhibit glutamine-5-
phosphoribosylpyrophosphate amidotransferase,
Inhibit Purine BioSynthesis
Fludarabine Monophosphate
is an analog of the purine adenine.
Fludarabine interferes with DNA polymerase, causing chain termination.
• Fludarabine is also immunosuppressive, with associated opportunistic infections resulting from fludarabine’s effect on T cells and a subsequent decrease in CD4 counts; prophylactic antibiotics and antiviral medications are recommended.
• Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia
Cladribine and pentostatin
are purine nucleoside analogs
.• Cladribine is resistant to inactivation by adenosine deaminase and triphosphorylated to an active form that is incorporated into DNA, resulting in inhibition of DNA synthesis and early chain termination.
Antifolates (Leucovorin
They carry one-carbon group in transfer
reactions that are required for purine and
thymidylic acid synthesis, and, in turn, for
formation of DNA and for cell division.
This drug bypasses the
metabolic block induced by DHFR inhibitors
Methotrexate
• It is effective for the treatment of a number of
cancers, including breast, head and neck,
leukemia, lymphoma, lung, osteosarcoma,
bladder, and trophoblastic neoplasms.
What’s Pemetrexed
It’s a multitargeted
antifolate that inhibits at least three biosynthetic
pathways in thymidine and purine synthesis.
Vinca alkaloids derived from, act as
Vincristine, vinblastine, and vinorelbine are natural alkaloids derived from the periwinkle (vinca) plant. They act as mitotic inhibitors, or “spindle poisons.”
Vinca alkaloids are used for treatment of
leukemias, lymphomas, sarcomas, and other solid tumors. Due to poor penetration of the BBB, vinca alkaloids are associated only occasionally with episodes of CNS toxicity.
Paclitaxel and docetaxel are
taxane plant alkaloids with
antimitotic activity.
How do DNA topoisomerase enzymes relieve torsional
strain?
during DNA unwinding by producing
strand breaks.
Camptothecin?
A plant alkaloid derived from
Camptotheca acuminata, is a potent inhibitor
of DNA topoisomerase I.
Doxorubicin, Daunorubicin, Idarubicin, and Epirubicin, what are they classified as
Anthracyclines have been classified as antitumor
antibiotics, but it is more accurate to refer to them as
intercalating topoisomerase inhibitors.
Alkylating Agents MOA
All of the alkylating agents work through the
covalent bonding of highly reactive alkyl groups
or substituted alkyl groups with nucleophilic
groups of proteins and nucleic acids.
Clinical use in world war 1
Cyclophosphamide and ifosfamide are
nitrogen mustard derivatives, and are widely
used alkylating agents.
Acrolein,
a metabolite of both cyclophosphamide and ifosfamide, has little antitumor activity, but is responsible for the
hemorrhagic cystitis of these agents.
The nitrosoureas are alkylating agents characterized by
lipophilicity and ability to cross the blood–brain barrier
• Dacarbazine and Temozolomide Dacarbazine (DTIC)
and temozolomide are nonclassic alkylating agents.
Both compounds undergo demethylation to the same active intermediate (monomethyl triazeno-imidazolecarboxamide [MTIC]) that interrupts DNA replication by causing methylation of guanine.
The platinum derivatives—cisplatin, carboplatin,
and oxaliplatin—
• The cytotoxicity of the platinum derivatives
depends on platinum binding to DNA and the
formation of intrastrand cross-links or adducts
between neighboring guanines.
