Download PURINE COMPOUNDS Both the pyrimidine bases (uracil, cytosine), and

PURINE COMPOUNDS
Both the pyrimidine bases (uracil, cytosine), and the purine bases (adenine, guanine) are building blocks
in the synthesis of DNA and RNA nucleotides. In the replication process, nucleotides are joined to one
another to form DNA strands. It is less clear how the purine antagonists function, but they may inhibit
normal production of DNA. It is conjectured that these purine antagonists stop synthesis by decreasing
the production of the purine bases or may be incorporated into the DNA strands during synthesis and
halt cell replication. Genetic mutation may lead to purine resistance. Fludarabine or 2-fluoro-ara-amp is
an antimetabolite of the purine class. It functions as a pro-drug . It is dephosphorylated and enters the
cancer cell. Fludarabine is rephosphorylated to F-ara-ATP. Upon incorporation into the DNA strand, it
halts strand lengthening. The drug is successfully used in treating refractory chronic lymphocytic and
chronic B cell leukemias, non-Hodgkin’s lymphoma and T- cell lymphoma. 6-Mercaptopurine (6-MP) is
another purine agent successfully used against acute lymphocytic leukemia. It is active in the S phase of
cell proliferation. Upon incorporation into DNA and RNA, the nucleic acids are rendered useless. 6-MP
may also act through inhibition of de novo synthesis of the purine bases. Without adequate amounts of
the purine bases, nucleotide production stops and the cancer cell dies. There are few clinically useful
purine antagonists.
6-MP
This drug can kill large numbers of cancer cells within the first 24 hours of treatment, spilling the cells'
contents into the blood. This can lead to electrolyte imbalances and tumor lysis syndrome, which can
result in serious kidney damage and other problems.
Fludarabine Mechanism of action
Every demonstrable cytotoxic mechanism of action of fludarabine requires the presence of F-ara-ATP.
The principal action of F-ara-ATP is in the inhibition of DNA synthesis.
Several specific enzymes involved with DNA synthesis are targets for inhibition by F-ara-ATP.20 In
particular, F-ara-ATP competes as an alternative substrate with the normal deoxynucleotide,
deoxyadenosine 5’-triphosphate (dATP), inhibiting directly the DNA polymerases. Furthermore F-araATP is able to inhibit DNA primase, an accessory protein that synthesizes an RNA primer required for
initiation of lagging strand synthesis by DNA polymerase.
F-ara-ATP is also an effective inhibitor of ribonucleotide reductase, resulting in lowering of cellular
deoxynucleotide pools which are maintained by this enzyme. This would change the ratio of F-ara-ATP
to dATP and consequently self-potentiates the DNA synthesis-directed actions of fludarabine.
In addition, F-ara-AMP is incorporated into DNA, particularly at the 3’-terminus, as purine analog. This
results in DNA ligase I inability to join it to an adjacent piece of DNA. Moreover, the free triphosphate
interacts with this enzyme to block AMP binding and ligation of single strands.
These actions on DNA ligase I have important implications for the actions of the drug on the function of
this enzyme in DNA replication and repair.
Together these actions are likely to result in complete inactivation of DNA synthesis followed by an
initiation of programmed cell death that ends in apoptosis of the cell.
Moreover, F-ara-ATP can induce cell death in quiescent cells in the absence of its incorporation into DNA
by the activation of the mitochondrial pathway of the apoptotic cascade.
PYRIMIDINE COMPOUNDS
Duschinsky synthesized and Heidelberger, in 1957, introduced 5-flurouracil (5-FU). 5-FU is a pyrimidine
base containing a fluoride atom at the 5 carbon position on the ring. Uracil is a naturally occurring
pyramidine base used in nucleic acid synthesis. It is converted to thymidine by enzyme action. 5-FU is
similar in structure to uracil and is converted to two active metabolites (FdUMP and FUTP) that inhibit
the activity of the enzyme thymidylate synthetase. The enzyme normally converts uracil to thymidine by
adding a methyl group at the fifth carbon of the pyrimidine ring. 5-FU mimics the natural base and
functions to inhibit DNA synthesis. The carbon group cannot be added because of the fluoride atom at
the five position. Normal DNA synthesis fails. dUTP and FdUTP are incorporated into DNA so that it
cannot function normally. In addition, FUTP is incorporated into RNA leading to faulty translation of the
RNA. Thus, the synthesis of multiple forms of RNA (messenger, ribosomal, transfer and small nuclear
RNAs) is blocked. These combined actions on DNA and RNA are cytotoxic to the rapidly dividing cancer
cells.
5-FU is used for the treatment of many malignancies: breast, head and neck, adrenal, pancreatic, gastric,
colon, rectal, esophageal, liver and G-U (bladder, penile, vulva, prostate) . 5-FU may be administered by
bolus IV infusion or continuous IV infusion over two days every 2-3 weeks or by oral ingestion. In
addition, it may be used to treat skin cancers (basal cell and keratosis) by topical application.
Other pyrimidine antagonists include: arabinosylcytosine, capecitabine, gemcitabine and decitabine.
Arabinosylcytosine or cytarabine is a deooxycytidine base compound that is converted to its active
metabolite, ara-CTP. This base is incorporated into DNA and causes strand termination. The cancer cell is
unable to divide. It is effective in acute non-lymphocytic, lymphocytic, myelogenous , and chronic
myelocytic leukemias, as well as leptominingeal carcinomatosis and non-Hodgkin’s lymphoma.
Capecitabine is an oral 5-FU pro-drug. It is converted to 5-FU by actions in liver and tumor cells. It is used
as adjuvant therapy in colon and breast metastasis. Gemcitabine is a ara-C pro drug which is activated
by intracellular phosphorylation. This inhibits DNA and RNA synthesis. It is a first line treatment of
pancreatic, metastatic breast, bladder, ovarian and non-small cell lung cancers. Finally, decitabine is
phosphorylated and directly incorporated into DNA. In cancer cells, it stops methylation by inhibiting
DNA methytransferase and induces cell death. It may also restore normal gene function controlling cell
proliferation. It is used therapeutically in myeloplastic syndrome.