Matrix metalloproteinase inhibitors: Present achievements and future prospects

Matrix metalloproteinases (MMPs) are a class of structurally related enzymes that function in the degradation of extracellular matrix proteins that constitute the pericellular connective tissue and play an important role in both normal and pathological tissue remodelling. Increased MMP activity is detected in a wide range of cancers and seems correlated to their invasive and metastatic potential. MMPs thus seem an attractive target for both diagnostic and therapeutic purposes. Several synthetic matrix metalloproteinase inhibitors (MMPIs) are currently being developed. Preclinical studies are promising as they suggest inhibition of several steps in the metastatic process. Marimastat is the first MMPI to enter comparative phase III trials after early clinical trials established the safety profile. Clinical trials will need to be specifically designed to optimally evaluate the therapeutic potential of this novel class of cytostatic drugs. Safety studies should consider the markedly different toxicity profile and determine the range of biologically active dosage, while efficacy studies should be performed in selected clinical settings with appropriate end-points. We review the present achievements in preclinical and clinical studies with MMPIs, discuss specific considerations for appropriate study design and reflect on the future prospects of this novel class of agents

Matrix metalloproteinase inhibitors: current developments and future perspectives

Malignant tumors are characterized by invasive growth and metastasis. To facilitate this invasive behavior, the enzymatic breakdown of the extracellular matrix (ECM) is a prerequisite. Many human tumors are characterized by locally increased concentrations of matrix metalloproteinases (MMPs), enzymes that are able to degrade this ECM. A vast number of matrix metalloproteinase inhibitors (MMPIs) have been developed in recent years and after extensive preclinical testing, the results of the first clinical studies with several of these compounds have recently been presented. In this review we will describe some of the basic concepts of the degradation of the ECM, with special emphasis on the role of MMPs in the progression of cancer. Furthermore we will review the results of preclinical and clinical studies with MMPIs and discuss their future perspective

Sensitive high-performance liquid chromatographic fluorescence assay for the quantitation of topotecan (SKF 104864-A) and its lactone ring-opened product (hydroxy acid) in human plasma and urine

A sensitive reversed-phase high-performance liquid chromatographic fluorescence method is described for the simultaneous determination of topotecan (I) and the hydrolysed lactone ring-opened product hydroxy acid (II) in plasma and for the determination of I in urine. To 250 μl of plasma, a 750-μl volume of cold methanol was added to stabilize the pH-dependent conversion of I into II. In plasma, the lower limit of quantitation (LLQ) for both compounds was 0.10 ng/ml. The between-day variation for I at the LLQ was 7.1% and for II was 5.5%. Prior to injection, urine samples were acidified with orthophosphoric acid and diluted with phosphate-buffered saline (PBS). In urine, the calibration curve for I was linear in the range of 10 to 250 ng/ml and the LLQ was 10 ng/ml. The assay was developed to enable pharmacological analysis of I, in on-going phase I and II studies, in patients with solid tumors

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

Possible lack of full cross-resistance of 5HT3 antagonists; a pilot study

We investigated the potential of cross-over to the serotonin receptor (5HT3) antagonist ondansetron after protection failure with tropisetron. Several cases of complete protection were observed. These limited data suggest that there is an indication for retreatment with a different 5HT3 antagonist after an initial failure to another and also stress the need and relevance for comparative studies between 5HT3 antagonists

A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumours

The ether lipid miltefosine (hexadecylphosphocholine) was orally given to patients with various tumours in a dose-finding study. All patients initially received a daily total dose of 100 mg, which in the absence of side-effects was increased to 150 mg and further to 200 mg. A total of 54 patients were entered and were evaluable for gastrointestinal toxicity. Nausea and vomiting were found to be dose-limiting; 22% of patients ultimately tolerated a dose of 100 mg, 59% tolerated a dose of 150 mg and 19% tolerated a dose of 200 mg. In addition 30% of patients developed renal dysfunction, which was thought to be related to the drug. No other toxities were observed. For further phase II studies it is recommended that one starts with a dose of 150 mg daily, divided over three administrations

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