These are analogues related to normal components of DNA or of coenzymes involved in nucleic acid synthesis. They competitively inhibit utilization of the normal substrate or get themselves incorporated forming dysfunctional macromolecules.
ANTIMETABOLITES
These are analogues related to normal components of DNA or of
coenzymes involved in nucleic acid synthesis. They competitively inhibit
utilization of the normal substrate or get themselves incorporated forming
dysfunctional macromolecules.
It is one of the oldest and highly efficacious antineoplastic
drugs; inhibits dihydrofolate reductase (DHFRase)—blocking the conversion of
dihydrofolic acid (DHFA) to tetrahydrofolic acid (THFA) which is an essential
coenzyme required for one carbon transfer reactions in de novo purine synthesis
and amino acid interconversions. The inhibition is pseudoirreversible because Mtx
has 50,000 times higher affinity for the enzyme than the normal substrate.
Methotrexate has cell cycle specific action— kills cells in S
phase; primarily inhibits DNA synthesis, but also affects RNA and protein
synthesis. It exerts major toxicity on bone marrow—low doses given repeatedly
cause megaloblastic anaemia, but high doses produce pancytopenia. Desquamation
and bleeding may occur in g.i.t.
Methotrexate is absorbed orally, 50% plasma protein bound,
little metabolized and largely excreted unchanged in urine. Salicylates,
sulfonamides, dicumerol displace it from protein binding sites. Aspirin and
sulfonamides enhance toxicity of Mtx by decreasing its renal tubular secretion.
The toxicity of Mtx
cannot be overcome by folic acid, because it will not be converted to the
active coenzyme form. However, Folinic
acid (N5 formyl THFA, cirtrovorum factor) rapidly reverses the effects.
Thymidine also counteracts Mtx toxicity.
Methotrexate is
apparently curative in choriocarcinoma: 15–30 mg/day for 5 days orally or 20–40
mg/m2 BSA i.m. or i.v. twice weekly. It is highly effective in maintaining
remission in children with acute leukaemias, but not good for inducing
remission: 2.5–15 mg/day. It is also useful in other malignancies, rheumatoid
arthritis, psoriasis and as immunosuppressant.
NEOTREXATE 2.5 mg tab,
50 mg/2 ml inj; BIOTREXATE 2.5 mg tab, 5, 15, 50 mg/vial inj.
The use of folinic
acid rescue has permitted much higher
doses of Mtx and has enlarged its scope to many difficult to treat neoplasms. A
nearly 100 times higher dose (250–1000 mg/m2 BSA) of Mtx is infused i.v. over 6
hours, followed by 3–15 mg i.v. calcium leucovorin within 3 hours, repeated as
required. This procedure can be repeated weekly.
These are highly effective
anti-neoplastic drugs. They are converted in the body to the corresponding mono-ribonucleotides
which inhibit the conversion of inosine monophosphate to adenine and guanine
nucleotides. There is also feedback inhibition of de novo purine synthesis.
They are especially
useful in childhood acute leukaemia, choriocarcinoma and have been employed in
some solid tumours as well. In acute leukaemia, both have been used in
combination regimens to induce remission and 6MP to maintain it as well.
Azathioprine
It has marked effect
on T-lymphocytes; suppresses cell mediated immunity (CMI) and is used primarily
as immuno-suppressant in organ transplantation, rheumatoid arthritis, etc.
All antipurines are
absorbed orally (though incompletely). Azathioprine and 6MP are metabolized by
xanthine oxidase; their metabolism is inhibited by allopurinol; dose has to be
reduced to ¼–½ if allopurinol is given concurrently. Thioguanine is not a
substrate for xanthine oxidase; follows a different (S-methylation) metabolic
path and its dose need not be reduced if allopurinol is given.
Methylation by thiopurine methyl transferase (TPMT) is an
additional pathway of 6MP metabolism. Genetic deficiency of TPMT makes the
individual more susceptible to 6MP toxicity, while over expression of TPMT is
an important mechanism of 6MP resistance by acute leukaemia cells. Toxicity of
azathioprine is also enhanced in TPMT deficiency.
The main toxic effect of antipurines is bone marrow depression,
which develops slowly. Mercaptopurine causes more nausea and vomiting than 6TG.
It also produces a high incidence of reversible jaundice. Hyperuricaemia occurs
with both; can be reduced by allopurinol.
6-Mercaptopurine: 2.5 mg/kg/day, half dose for maintenance; PURINETHOL, EMPURINE
50 mg tab.
6Thioguanine: 100–200 mg/m2/day
for 5–20 days; 6TG 40 mg tab.
Azathioprine: 3–5 mg/kg/day, maintenance 1–2 mg/kg/ day; IMURAN, TRANSIMUNE,
AZOPRINE 50 mg tab.
Fludarabine
This newer purine
anti-metabolite is phosphorylated
intracellularly to the active triphosphate form which then inhibits DNA
polymerase as well as gets incorporated to form dysfunctional DNA. Tumour cell
apoptosis is promoted by multiple mechanisms confering activity even in slow
growing neoplasm. It is indicated in chronic lymphatic leukaemia and non-Hodgkin’s
lymphoma that have recurred after treatment. Prominent adverse effects are
chills, fever and vomiting after injection, myelosuppression and opportunistic
infections.
Dose: 25 mg/m2 BSA daily for 5 days every 28 days by
i.v. infusion
FLUDARA 50 mg/vial
inj.
Pyrimidine analogues have varied applications as antineo-plastic,
antifungal and antipsoriatic agents.
Fluorouracil (5-FU) is converted in the
body to the corresponding
nucleotide 5fluoro2deoxyuridine monophosphate, which inhibits thymidylate
synthase and blocks the conversion of deoxyuridilic acid to deoxythymidylic
acid. Selective failure of DNA synthesis occurs due to nonavailability of
thymidylate: thymidine can partially reverse its toxicity. Fluorouracil itself gets
incorporated into nucleic acids and this may contribute to its toxicity. Even resting
cells are affected, though rapidly multiplying ones are more susceptible.
Dose: 1 g orally on
alternate days (6 doses) then 1 g weekly or
12 mg/kg/day i.v. for 4 days—6 mg/kg i.v. on alternate days; FLURACIL, FIVE FLURO
250 mg cap, 250 mg/5 ml for i.v. inj, also 1% topical solution.
It has been
particularly used for many solid tumours—breast, colon, urinary bladder, liver,
etc. Topical application in cutaneous basal cell carcinoma has yielded
gratifying results.
It is phosphorylated in
the body to the corresponding
nucleotide which inhibits DNA synthesis. The triphosphate of cytarabine is an
inhibitor of DNA polymerase and blocks generation of cytidilic acid. However,
it is now believed that its incorporation into DNA is more important for the
expression of cellular toxicity. It also interferes with DNA repair. Cytarabine
is cell cycle specific and acts primarily during S phase. Its main use is to
induce remission in acute leukaemia in children, also in adults. Other uses
are—Hodgkin’s disease and non-Hodgkin lymphoma.
Dose: 1.5–3 mg/kg i.v. BD
for 5–10 days (also by continuous i.v. infusion): CYTARABIN, CYTROSAR, CYTABIN, 100, 500,
1000 mg inj.
Both 5FU and
cytarabine exert primary toxicity on bone marrow and g.i.t. Genetic deficiency
of dihydropyrimidine dehydrogenase (DPD) predisposes to severe 5FU toxicity.
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