244 research outputs found
Topoisomerase I inhibitors: clinical studies on oral administration and/or combinations with cisplatin
The 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
Stability of boundaries between response options of response scales: Does 'very happy' remain equally happy over the years?
The differences between response scales in number and wording of response options make it hard to compare data from survey research and to perform research syntheses. A recent method that we have developed to tackle this problem is rooted in the idea that the transition points on a bounded continuum, on which verbal response options from a primary scale transit from one point to another, for instance from ‘happy’ to ‘very happy’, remain unchanged over time. The idea behind this is that although people may change their perception of, for example, their own happiness intensity over time, they are assumed not to change the degree of appreciation they attribute to the terms used to label response options. This is an important assumption for research syntheses that requires that everything remains unchanged, except for the change of interest. It means that if our method is applied to measurements at distinct points in time, differences in estimates of the mean and standard deviation can be attributed solely to changes in the frequency distributions on the primary scale. In this paper we apply the method to happiness and show that it is reasonable to assume that the transition points between the response options are stable over time. Keywords: verbal response scales; comparability; scale transformation; beta distribution; reference distribution; research synthesi
Ecthyma gangrenosum caused by Pseudomonas aeruginosa in a patient with astrocytoma treated with chemotherapy
Ecthyma gangrenosum, presenting as embolic lesions caused by Pseudomonas aeruginosa infection, has distinct pathognomonic features and a high mortality rate in patients with bacteremia, but when recognized early is easily treated. In this case report we describe this disseminated infection in an adult patient treated with chemotherapy for an astrocytoma
Moving molecular targeted drug therapy towards personalized medicine: Issues related to clinical trial design
With the event of new Molecular targets, clinical trial design requirements to perform these trials are changing. This paper discusses some of the considerations that need to be taken into account when designing a trial, including those trials that assess combinations of targets
Topotecan lacks third space sequestration
The objective of this study was to determine the influence of pleural and
ascitic fluid on the pharmacokinetics of the antitumor camptothecin
derivative topotecan. Four patients with histological proof of malignant
solid tumor received topotecan (0.45 or 1.5 mg/m2) p.o. on several
occasions in both the presence and absence of third space volumes. Serial
plasma and pleural or ascitic fluid samples were collected during each
dosing and analyzed by high-performance liquid chromatography for both the
intact lactone form of topotecan and its ring-opened carboxylate form. The
apparent topotecan clearance demonstrated substantial interpatient
variability but remained unchanged within the same patient in the presence
[110 +/- 55.6 liters/ h/m2 (mean +/- SD of eight courses)] or absence of
pleural and ascitic fluid [118 +/- 31.1 liters/h/m2 (mean +/- SD of seven
courses)]. Similarly, terminal half-lives and area under the
concentration-time curve ratios of lactone:total drug in plasma were
similar between courses within each patient. Topotecan penetration into
pleural and ascitic fluid demonstrated a mean lag time of 1.61 h (range,
1.37-1.86 h), and ratios with plasma concentration increased with time
after dosing in all patients. The mean ratio of third space topotecan
total drug area under the concentration-time curve to that in plasma was
0.55 (range, 0.26-0.87). These data indicate that topotecan can be safely
administered to patients with pleural effusions or ascites and that there
is substantial penetration of topotecan into these third spaces, which may
prove beneficial for local antitumor effects
Factors involved in prolongation of the terminal disposition phase of SN-38: clinical and experimental studies
The active metabolite of irinotecan (CPT-11),
7-ethyl-10-hydroxycamptothecin (SN-38), is either formed through enzymatic
cleavage of CPT-11 by carboxyl esterases (CEs) or through cytochrome P-450
3A-mediated oxidation to 7-ethyl-10-[4-(1-piperidino)-1-amino]
carbonyloxycamptothecin (NPC) and a subsequent conversion by CE. In the
liver, SN-38 is glucuronidated (SN-38G) by UGT1A1, which also conjugates
bilirubin. Fourteen patients were treated with 350 mg/m2 CPT-11, and we
performed pharmacokinetic analysis during a 500-h collection period. The
half-life and area under the plasma concentration-time curve of SN-38 were
47+/-7.9 h and 2.0+/-0.79 microM x h, respectively, both representing a
2-fold increase as compared with earlier reported estimates (A. Sparreboom
et al, Clin. Cancer Res., 4: 2747-2754, 1998). As an explanation for this
phenomenon, we noted substantial formation of SN-38 from CPT-11 and NPC by
plasma CE, consistent with the low circulating levels of NPC observed. In
addition, transport studies in Caco-2 monolayers indicated that
nonglucuronidated SN-38 could cross the membrane from apical to
basolateral, indicating the potential for recirculation processes that can
prolong circulation times. Interestingly, individual levels of fecal
beta-glucuronidase, which is known to mediate SN-38G hydrolysis, were not
related to any of the SN-38 kinetic parameters (r = 0.09; P = 0.26),
suggesting that interindividual variation in this enzyme is unimportant in
explaining SN-38 pharmacokinetic variability. We have also found, in
contrast to earlier data, that SN-38G/SN-38 plasma concentration ratios
decrease over time from approximately 7 (up to 50 h) to approximately 1
(at 500 h). This decrease could be explained by the fact that
glucuronidation of SN-38 and bilirubin is increasingly competitive at
lower drug levels. In addition, no evidence was found for SN-38G transport
through the Caco-2 cells. Our findings indicate that until now the
circulation time of SN-38 has been underestimated. This is of crucial
importance to our understanding of the clinical action of CPT-11 and for
future pharmacokinetic/pharmacodynamic relationships
Inter- and intrapatient variability in oral topotecan pharmacokinetics: implications for body-surface area dosage regimens
Anticancer drugs still are dosed based on the body-surface area (BSA) of
the individual patient, although the BSA is not the main predictor of the
clearance for the majority of drugs. The relevance of BSA-based dosing has
not been evaluated for topotecan yet. A retrospective pharmacological
analysis was performed of kinetic data from four clinical Phase I studies
in which topotecan was administered p.o. as a single agent combined with
data from a combination study of topotecan and cisplatin. A strong
correlation (r = 0.91) was found between the area under the plasma
concentration time curve of the lactone and carboxylate forms of topotecan
by plotting 326 data sets obtained from 112 patients receiving oral
topotecan at dose levels ranging from 0.15-2.70 mg/m2. The intrapatient
variability, studied in 47 patients sampled for 3 or more days, for the
apparent lactone clearance, ranged from 7.4-69% (mean, 24 +/- 13%; median,
20%). The interpatient variabilities in the lactone clearance, calculated
with the data of all studied patients, expressed in liter/h/m2 and in
liter/h were 38% and 42%, respectively. In view of the relatively high
inter- and intrapatient variabilities in topotecan clearance, in contrast
to a variability of only 12% in the BSA of the studied patients, no
advantage of BSA-based dosing was found over fixed dose regimens
Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients
This study was designed to evaluate irinotecan (CPT-11) disposition and
pharmacodynamics in the presence and absence of the broad-spectrum
antibiotic neomycin. Seven evaluable cancer patients experiencing diarrhea
graded > or =2 after receiving CPT-11 alone (350 mg/m(2) i.v. once every 3
weeks) received the same dose combined with oral neomycin at 1000 mg three
times per day (days -2 to 5) in the second course. Neomycin had no effect
on the systemic exposure of CPT-11 and its major metabolites (P > or =
0.22). However, it changed fecal beta-glucuronidase activity from 7.03 +/-
1.76 microg/h/mg (phenolphthalein assay) to undetectable levels and
decreased fecal concentrations of the pharmacologically active metabolite
SN-38. Although neomycin had no significant effect on hematological
toxicity (P > 0.05), diarrhea ameliorated in six of seven patients (P =
0.033). Our findings indicate that bacterial beta-glucuronidase plays a
crucial role in CPT-11-induced diarrhea without affecting enterocycling
and systemic SN-38 levels
- …