374 CANCER CHEMOTHERAPY
- myelosuppression – usually thrombocytopenia;
- nervous system effects – cerebellar syndrome, peripheral
neuropathy.
Pharmacokinetics
Cisplatinrequires the replacement of the two chloride atoms
with water (‘aquation’) to become active. This process takes
approximately 2.5 hours. Plasma disappearance of cisplatinis
multiphasic and traces of platinum are detectable in urine
months after treatment.
Drug interactions
Additive nephrotoxicity and ototoxicity occurs with amino-
glycosides or amphotericin.
ANTIMETABOLITESAntimetabolites are structural analogues of, and compete
with, endogenous nucleic acid precursors. Unfortunately, the
pathways blocked by antimetabolites are not specific to neo-
plastic cells. Thus, their selectivity for malignant cells is only
partial. They act in the S-phase of the cell cycle.
ANTIFOLATE ANALOGUES
METHOTREXATE
Uses
Methotrexate is curative for choriocarcinoma, also induces
remission in acute lymphocytic leukaemia and is often active in
breast cancer, osteogenic sarcoma and head and neck tumours.
Methotrexateis also an immunosuppressant (Chapters 26 and
50) and is used to inhibit cellular proliferation in severe psoria-
sis (Chapter 51). There are several different dosage schedules,
several of which require co-administration of folinic acid (see
Figure 48.5).
Mechanism of action
Folic acid is required in the synthesis of thymidylate (a
pyrimidine) and of purine nucleotides and thus for DNA syn-
thesis (Figure 48.5). Methotrexateis a very slowly reversible
competitive inhibitor of dihydrofolate reductase (DHFR). The
affinity of DHFR for methotrexateis 100 000 times greater than
that for dihydrofolate. Thus, methotrexateprevents nucleic
acid synthesis and causes cell death. Folinic acid circumvents
this biosynthetic block and thus non-competitively antagonizes
the effect of methotrexate.Determinants of methotrexate toxicity
These consist of:- a critical extracellular concentration for each target organ;
- a critical duration of exposure that varies for each organ.
For bone marrow and gut, the critical plasma concentration
is 2 10 ^8 Mand the time factor is approximately 42 hours.
Both factors must be exceeded for toxicity to occur in these
organs. The severity of toxicity is proportional to the length of
time for which the critical concentration is exceeded and is
independent of the amount by which it is exceeded.
Folinic acid rescue bypasses the dihydrofolate reductase
blockade and minimizes methotrexatetoxicity. Some malig-
nant cells are less able to take up folinic acid than normal cells,
thus introducing a degree of selectivity. Rescue is commenced
24 hours after methotrexateadministration and continued until
the plasma methotrexateconcentration falls below 5 10 ^8 M.
Monitoring of the plasma methotrexateconcentrations has
improved the safe use of this drug and allows identification of
patients at high risk of toxicity. If a patient develops severe tox-
icity with protracted elevation of methotrexateconcentrations,
methotrexatemetabolism can be rapidly increased by adminis-
tering an inactivating enzyme, namely carboxypeptidase-G2
(not routinely available in the UK), when methotrexateconcen-
trations exceed 1 10 ^7 M.
Table 48.6:Comparative pharmacology of some platinum compounds
Drug Standard dosing regimen Side effects Pharmacokinetics Additional comments
Carboplatin (CBP) i.v. dose is calculated based Like cisplatin, but less Activation slower than Anti-tumour spectrum
on the desired AUC by the vomiting and cisplatin t1/22–3 h, 60–70% similar to that of cisplatin
Calvert formula nephrotoxicity. Low excreted in the urine in
potential for ototoxicity first 24 h
and neuropathyOxaliplatin i.v. administration. Mild bone marrow Biotransformed in blood. Third generation
Bulky DACH carrier ligand. suppression. Little Renal and tissue platinum analogue. Activity
Unlike cisplatin or carboplatin nephro- or ototoxicity, elimination. Good tissue profile differs from cisplatin.
cf. cisplatinbut cold-induced distribution due to DACH Ovarian, colorectal,
neurosensory toxicity pancreatic cancer, and
mesotheliomaCDDP, cisplatin; DACH, diaminocyclohexane.