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

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

Gender and obesity

The effects of olanzapine on the symptomatology of children with pervasive developmental disorder with emphasis on problems of communication and the safety of the drug were investigated in a 3-month open-label, open-dosage study. Participating in the study were 25 children age 6 to 16 years with a diagnosis of either autistic disorder or pervasive developmental disorder not otherwise specified. Psychometric measures included the Clinical Global Impression of Severity/Improvement, the Aberrant Behavior Checklist, and the TARGET (a checklist of five target symptoms). Communication skills were assessed during behavioral analysis of a playroom session. Safety measures included clinical chemistry variables, electrocardiography, the SimpsonAngus Neurological Rating Scale, the Barnes Akathisia Scale, and vital signs. Twenty-three children completed the study and showed significant improvement on three subscales of the Aberrant Behavior Checklist (Irritability, Hyperactivity, and Excessive Speech) and the TARGET. The final mean dose was 10.7 mg/day. Several aspects of communication were also improved after olanzapine treatment. However, only three children were considered responders in terms of the Clinical Global Impression of Severity/Improvement scores. The most important adverse events were weight gain, increased appetite, and loss of strength. Three children showed extrapyramidal symptoms that disappeared after the dose was lowered. Thus, while olanzapine was a relatively safe medication in children, its clinical relevance in children with pervasive developmental disorder may be limited

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