Q22

In clinical trials Carboplatin was
MORE efficacious than Cisplatin.

Up-regulation of NER pathway
results in increased platinum DNA
adduct repair.
• Comparative trials have demonstrated
equivalent activity between cisplatin and
carboplatin in the management of ovarian
cancer.
• The equivalence between cisplatin and carbo-
platin doublets in adjuvant therapy for non-
small cell lung or limited stage small cell lung
cancer remains unclear.
• Studies that substituted carboplatin over
cisplatin in combination with etoposide
with/without bleomycin for the treatment of
good-risk germ cell tumors demonstrated that
cisplatin is superior for relapse-free survival.
• Comparative trials of cisplatin or carboplatin
with 5-fluorouracil (5-FU) in the management
of squamous cell head and neck cancer also
tend to support the use of cisplatin with
superior rates of response over carboplatin.
platinum drug resistance
• (a) failure to accumulate adequate drug in order to pro- duce
significant DNA damage
• (b) failure of cell death post-platinum binding to DNA.
• Increased levels of thiols such as glutathione or metallothioneins,
represent major causes of failure to accumulate adequate drug
concentration to produce meaningful levels of cell kill.
• Failure of cell death post-platinum–DNA binding may be explained
by relevant mechanisms that are involved in DNA repair.

• One such mechanism is the nucleotide excision repair (NER) path-
way. Up regulation of the NER pathway results in increased
platinum–DNA adduct repair, contributing to platinum resistance.
Several markers exist to indicate the activity of the NER pathway,
such as the excision repair cross complement 1 (ERCC1).
Q23
• Presence of ERCC 1 gene expression in NSCLC
has been shown to directly affect outcome in
patients treated with platinum.


• Protein or mRNA expression of ERCC1, or poly
morphisms affecting ERCC1 gene, can possibly
be used to indicate NER activity.
• Presence of ERCC1 protein expression in non-
small cell lung cancer has been shown to
inversely affect outcome in patients treated
with platinum-based regimens.
Q24
• Patients with BRCA1 and BRCA2 gene
mutations are highly sensitive to Cisplatin.

• These patients develop tumours which lack
the capability for homologous recombination
repair (HR).

• Antimetabolites interfere with the synthesis of
DNA and RNA.

• Most antimetabolites act during the S phase
of the cell cycle, when cell proliferation is
more prominent, but, depending on their
mechanism of action, they may act in the G1
or G2/M phase.
• Aggressive hydration with IV normal saline
(2.5 to 3.5 L of fluid per m2 per 24 hrs,
beginning 12 hrs before MTX infusion and
continuing for 24 to 48 hrs),
• Alkalinization of the urine (45 to 50 mEq
sodium bicarbonate per litre of IV fluids) to
keep the urinary pH >7.0 at the time of drug
infusion, is recommended before and in the
first 48–72 hrs follow- ing HD-MTX (>1 g/m2).
• Urinary alkalinization facilitates MTX renal
excretion by increasing solubility and avoiding
precipitation in the renal tubules. Sodium
bicarbonate is taken to keep the urinary pH
>7.0. Monitoring of plasma levels is essential
when using the HD regimen to control the late
phase of distribution, which is the most
important in terms of toxicity.

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