These compounds produce highly reactive carbonium ion intermediates which transfer alkyl groups to cellular macromolecules by forming covalent bonds. The position 7 of guanine residues in DNA is especially susceptible, but other molecular sites are also involved.
ALKYLATING AGENTS
These compounds
produce highly reactive carbonium ion intermediates which transfer alkyl groups
to cellular macromolecules by forming covalent bonds. The position 7 of guanine
residues in DNA is especially susceptible, but other molecular sites are also
involved. Alkylation results in cross linking/abnormal base pairing/ scission
of DNA strand. Cross linking of nucleic acids with proteins can also take
place.
Alkylating agents have
cytotoxic and radiomimetic (like ionizing radiation) actions. Many are cell
cycle nonspecific, i.e. act on dividing as well as resting cells. Some have CNS
stimulant and cholinergic properties.
It is the first nitrogen mustard; highly reactive and local
vesicant—can be given only by i.v. route. It produces many acute effects like
nausea, vomiting and haemodynamic changes. Extravasation during i.v. injection
may cause sloughing.
Dose: 0.1 mg/kg i.v. daily x
4 days; courses may be repeated at
suitable intervals.
MUSTINE 10 mg dry
powder in vial.
It is inactive as
such: produces few acute effects and is not locally damaging. Transformation
into active metabolites (aldophosphamide, phosphoramide mustard) occurs in the
liver, and a wide range of antitumour actions is exerted. It has prominent
immunosuppressant property. Thus, it is one of the most popular anticancer
drugs. It is less damaging to platelets, but alopecia and cystitis (due to
another metabolite acrolein) are prominent. Chloramphenicol retards the
metabolism of cyclophosphamide.
Dose: 2–3 mg/kg/day oral;
10–15 mg/kg i.v. every 7–10 days,
i.m. use also possible.
ENDOXAN, CYCLOXAN 50
mg tab; 200, 500, 1000 mg inj.
Ifosfamide
This congener of
cyclophosphamide has a longer and dose-dependent
t½. It has found utility in bronchogenic, breast, testicular, bladder, head and
neck carcinomas, osteogenic sarcoma and some lymphomas. The dose limiting toxicity
of ifosphamide is haemorrhagic cystitis. To prevent the same mesna is routinely given with it. Mesna
is a –SH compound that is excreted in urine—binds and inactivates the
vasicotoxic metabolites of ifosfamide and cyclophosphamide. Ifosfamide causes
less alopecia and is less emetogenic than cyclophosphamide.
HOLOXANUROMITEXAN 1 g
vial + 3 amps of mesna 200 mg inj.; HOLOXAN, IPAMIDE 1 g inj.
Chlorambucil
It is a very slow
acting alkylating agent, especially active
on lymphoid tissue: Myeloid tissue is largely spared. It is the drug of choice
for long-term maintenance therapy for chronic lymphatic leukaemia; Hodgkin’s disease
and some solid tumours also resolve. It has some immunosuppressant property.
Dose: 4–10 mg (0.1–0.2
mg/kg) daily for 3–6 weeks, then 2 mg
daily for maintenance; LEUKERAN 2, 5 mg tab.
Melphalan
It is very effective
in multiple myeloma and has been used
in advanced ovarian cancer. Bone marrow depression is the most important
toxicity. Infections, diarrhoea and pancreatitis are the complications.
Dose: 10 mg daily for 7
days or 6 mg/day for 2–3 weeks— 4
weeks gap—2 to 4 mg daily for maintenance orally. Also used for regional
perfusion in malignant melanoma. ALKERAN 2, 5 mg tab, 50 mg per vial for inj.
Thio-TEPA
It is an ethylenimine:
does not require to form an
active intermediate. It has high toxicity: seldom used now.
Dose: 0.3–0.4 mg/kg i.v. at
1–4 week intervals.
THIOTEPA 15 mg per
vial inj.
It is highly specific
for myeloid elements; granulocyte
precursors being the most sensitive, followed by those of platelets and RBC. It
produces little effect on lymphoid tissue and g.i.t. Hyperuricaemia is common
and pulmonary fibrosis is a specific adverse effect. Sterility also occurs. It
is the drug of choice for chronic myeloid leukaemia.
Dose: 2–6 mg/day (0.06
mg/kg/day) orally.
MYLERAN, BUSUPHAN 2 mg
tab.
These are highly lipid
soluble alkylating agents with
a wide range of antitumour activity. They cross bloodbrain barrier—are
effective in meningeal leukaemias and brain tumours. Nausea, vomiting are
common and CNS effects also occur. Bone marrow depression is peculiarly delayed,
taking nearly 6 weeks to develop. Visceral fibrosis and renal damage can occur:
Lomustine (CCNU):
100–130 mg/m2 BSA single oral dose every 6 weeks; LOMUSTINE 40, 100 mg
cap.
It is different from
other alkylating agents in
having primary inhibitory action on RNA and protein synthesis (others mainly
affect DNA). It is activated in the liver. The most important indication is malignant
melanoma; also used in Hodgkin’s disease. Nausea and vomiting are prominent
side effects.
Dose: 3.5 mg/kg/day i.v. for
10 days, repeat after 4 weeks. DACARIN 100, 200, 500
mg inj; DACARZINE 200 mg/ vial inj.
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