Title: Topoisomerase I inhibitors: clinical studies on oral administration and/or combinations with cisplatin
Abstract:textabstractThe topoisomerases were discovered in 1971, but it was not until the 1980s that the
significance of these enzymes as potential therapeutic targets was appreciated.
Topoisomerase I plays a ...textabstractThe topoisomerases were discovered in 1971, but it was not until the 1980s that the
significance of these enzymes as potential therapeutic targets was appreciated.
Topoisomerase I plays a crucial role in the normal replication of DNA. In its
physiological state in the chromosome, the DNA helix is supercoiled. Replication
requires transient relaxation and unwinding of the parent DNA. In order to achieve
this, transient cleavage of the DNA is required mediated by the formation of a
cleavable-complex consisting of a covalent intermediate between topoisomerase I
and DNA, allowing passage of the intact strand. The enzyme-bridged breaks are
resealed afterwards. Topoisomerase I inhibitors stabilize the cleavable complex.
thereby inhibiting the religation step. This results in collision of the replication
fork and, finally, in double strand breaks and cell death.
In the early 1970s, the parent compound camptothecin, an extract from the
Camptotheca acuminata, an oriental tree, entered clinical studies. Although
some antitumor activity was observed, severe and unpredictable toxicities prevented
further clinical development. It was not until the discovery of the mechanism of action
of camptothecin, that numerous semi-synthetic camptothecin analogues were
developed with a more predictable toxicity profile and better water-solubility and
entered clinical trials. The first two of these, irinotecan and topotecan, were recently
registered for different indications.
Preclinical studies with different topoisomerase I inhibitors showed more antitumor
efficacy with prolonged low dose exposure to the drugs, and in animal models, low
dose exposure resulted in less toxicity. These. preclinical findings were the
stimulus for early clinical studies with low dose continuous infusion of topoisomerase
I inhibitors in patients with advanced solid tumors. However, the use of
prolonged continuous infusion schedules is associated with the complications of the
use of central venous catheters and the cost of administration is high. Aside from
economic considerations, patients with advanced malignancies, when asked,
preferred oral administration of cytotoxic drugs over the intravenous formulation,
provided that no significant reductions in efficacy or duration of response would result
from this mode of treatment. The reasons for patients' preferences included
convenience, current concern or previous difficulties with intravenous access lines, or
preference to control the chemotherapy administration environment. An oral
formulation would also provide a more convenient method for prolonged drug
administration.
Considering their mode of action, topoisomerase I inhibitors may also interfere in
processes involved in DNA repair.This renders them attractive for further investigations in combination with other cytostatic agents, especially DNA-damaging
agents. Preclinical studies have revealed synergism between topoisomerase I
inhibitors and platinum-derivatives, topoisomerase II inhibitors and taxanes in a
number of different human cancer cell lines and xenografts.
This thesis includes clinical and pharmacological studies on the oral administration of
the novel topoisomerase I inhibitor 9-amino-20(S)-camptothecin and studies on the
combination of cisplatin with the topoisomerase I inhibitors irinotecan and oral
topotecan.Read More
Publication Year: 1999
Publication Date: 1999-10-13
Language: en
Type: article
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Landing Page URL: https://repub.eur.nl/pub/20053/991013_JONGE, Maja Johanna Antonia de.pdf