Overview of gemcitabine triplets in metastatic bladder cancer.

For more than a decade the MVAC regimen has been gold standard chemotherapy in bladder cancer, albeit that the toxicity associated with this therapy hampered its use in many of the typical elderly patients with metastatic disease. New active agents have been identified, combinations of these new agents with platinum compounds (doublets) followed, and results have become available of a phase III randomized trial of the gemcitabine and cisplatin doublet versus MVAC, that has revealed an efficacy-toxicity profile in favor of the gemcitabine-cisplatin regimen. During the conduct of this study, investigators in Spain and in the United States have incorporated both gemcitabine and paclitaxel in either cisplatin- or carboplatin based triplet regimens that, albeit thus far only in phase II studies, have indicated notable activity and favorable median survival figures, particularly in patients with visceral disease.

Phase I and pharmacokinetic studies of PNU-159548, a novel alkycycline, administered intravenously to patients with advanced solid tumours.

PNU-159548 (4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin) is the lead compound of a novel class of cytotoxic agents (alkycyclines) with a unique mechanism of action combining DNA intercalation with alkylation of guanines in the DNA major groove. The objectives of two phase I studies were to assess the dose-limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD) and to study the pharmacokinetics (PKs) of PNU-159548 and its active metabolite PNU-169884 when administered intravenously (i.v.

Dose-dense cisplatin/paclitaxel. a well-tolerated and highly effective chemotherapeutic regimen in patients with advanced ovarian cancer.

A randomised phase I/II trial with weekly cisplatin 70 mg/m(2) (days 1, 8, 15, 29, 36, 43) in combination with escalating doses of paclitaxel either 4-weekly or weekly was conducted in 49 patients with ovarian cancer; patients were chemotherapy-nai;ve or had a first relapse after platinum-based chemotherapy. Paclitaxel could be safely escalated to 225 mg/m(2) 4-weekly or 100 mg/m(2) weekly, with fatigue as the major adverse event. Myelosuppression, renal toxicity and neurotoxicity were mild to moderate.

Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan.

Topotecan and irinotecan (CPT-11) are both anticancer agents active in the inhibition of topoisomerase I, an enzyme involved in DNA replication and RNA transcription. During the last decades, an immense amount of research into this class of anticancer agents has been conducted, the positive results of which led to the clinical use of topotecan and CPT-11 in ovarian cancer and colorectal cancer, respectively. Here, we review the currently most important pharmacologic aspects of these drugs, including their mechanisms of action, metabolism, activity- and toxicity-profiles and mechanisms of resistance, to provide a global insight into their pharmacology.

Effects of impaired renal function on the pharmacokinetics and toxicity of i.v. ZD9331, a novel non-polyglutamated thymidylate synthase inhibitor, in adult patients with solid tumors.

ZD9331 is a potent thymidylate synthase inhibitor. Renal and hepatic clearances were found to be important routes of elimination. The objectives of this pharmacologic trial were to investigate the effect of renal impairment on the pharmacokinetics of ZD9331, to study the toxicity profile and to document any antitumor effects of ZD9331 when administered i.

Modulation of irinotecan metabolism by ketoconazole.

Purpose: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients.

Determination of the docetaxel vehicle, polysorbate 80, in patient samples by liquid chromatography-tandem mass spectrometry.

A new simple method was developed for the quantitative determination of the docetaxel (Taxotere) vehicle, polysorbate 80 (Tween 80), in human plasma. Calibration curves were constructed in the range of 1-100 microg/ml, using paclitaxel (0.01 mM) as internal standard, and were analyzed using a power fit with equal weighting.

Differential effects of fibroblast growth factors on expression of genes of the plasminogen activator and insulin-like growth factor systems by human breast fibroblasts.

In breast stroma urokinase plasminogen activator (uPA) is predominantly expressed by fibroblasts located in the near vicinity of tumor cells, and fibroblast-derived insulin-like growth factor-1 (IGF-1) may be involved in inhibiting the expression of uPA in these fibroblasts. To investigate a possible role for fibroblast growth factors (FGFs), we evaluated the expression of components of the PA system and the IGF system in normal and tumor-tissue-derived human breast fibroblasts exposed to various FGFs in vitro. mRNA analysis revealed that FGF-1, FGF-2 and FGF-4 induced the mRNA expression levels of uPA, tPA, uPAR, PAI-1 and PAI-2, and reduced those of IGF-1, IGF-1R, IGF-2R and IGFBP-4, without significantly affecting the levels of IGFBP-3, IGFBP-5 and IGFBP-6 mRNA.

Disposition of docetaxel in the presence of P-glycoprotein inhibition by intravenous administration of R101933.

Recently, a study of docetaxel in combination with the new orally administered P-glycoprotein (P-gp) inhibitor R101933 showed that this combination was feasible. However, due to the low oral bioavailability of R101933 and high interpatient variability, no further attempts to increase the level of P-gp inhibition were made. Here, we assessed the feasibility of combining docetaxel with intravenously (i.

Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel.

It has been hypothesized that the paclitaxel vehicle Cremophor EL (CrEL) is responsible for nonlinear drug disposition by micellar entrapment. To gain further insight into the role of CrEL in taxane pharmacology, we studied the pharmacokinetics of paclitaxel in the presence and absence of CrEL after i.p.

Capecitabine in breast cancer: current status.

Anthracyclines, together with taxanes, are at present the most active agents in metastatic breast cancer, while single-agent, bolus 5-fluorouracil (5-FU) is not very active in this setting. In view of encouraging results and tolerable toxicity of continuous infusion of 5-FU in gastrointestinal cancer, innovative oral 5-FU agents such as capecitabine have been developed. Capecitabine is a prodrug that is converted into the active compound 5-FU preferentially at the tumor site.

Structural identification and biological activity of 7-methyl-10,11-ethylenedioxy-20(S)-camptothecin, a photodegradant of lurtotecan.

An additional chromatographic peak was observed in plasma samples of patients receiving NX 211, a liposomal formulation of the topoisomerase I inhibitor lurtotecan. We have isolated and purified this product by sequential solid-phase extractions, and we report its structure and cytotoxicity relative to lurtotecan and related agents. Nuclear magnetic resonance data indicate that cleavage of the piperazino moiety occurred at the N-C bond of the B-ring, yielding 7-methyl-10,11-ethylenedioxy-20(S)-camptothecin (MEC).

Determination of topotecan in human whole blood and unwashed erythrocytes by high-performance liquid chromatography.

A reversed-phase HPLC method for the quantitative determination of total topotecan in human whole blood and unwashed erythrocytes has been developed and validated in terms of sensitivity, specificity, precision and accuracy. Linear calibration curves were constructed in the range of 0.20 to 50.

Comparative pharmacokinetics of unbound paclitaxel during 1- and 3-hour infusions.

Purpose: The paclitaxel vehicle Cremophor EL (CrEL) profoundly influences the cellular distribution of paclitaxel in human blood in vitro by a concentration-dependent decrease of the unbound drug fraction. Because CrEL clearance increases by extending the infusion duration from 3 to 24 hours, we hypothesized that exposure to unbound paclitaxel might also be schedule-dependent.

Patients And Methods: CrEL and unbound paclitaxel pharmacokinetics were prospectively analyzed in 29 patients with advanced solid tumors treated with paclitaxel 100 mg/m(2) given as a 1-hour (n = 15) or 3-hour (n = 14) intravenous infusion.

Impact of body-size measures on irinotecan clearance: alternative dosing recommendations.

Purpose: To evaluate relationships between various body-size measures and irinotecan (CPT-11) clearance and metabolism in cancer patients, and to provide future dosing recommendations for this agent.

Patients And Methods: Pharmacokinetic data were obtained from 82 adult patients (50 men, 32 women; median age, 54 years) receiving CPT-11 as a 90-minute intravenous infusion (dose range, 175 to 350 mg/m(2)). In each patient, plasma samples were collected at timed intervals in the first administration of a 3-week schedule, and CPT-11 and its metabolite, SN-38, were measured by a liquid chromatographic assay.

Modulation of cisplatin pharmacodynamics by Cremophor EL: experimental and clinical studies.

The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.

The use of oral cytotoxic and cytostatic drugs in cancer treatment.

Although with a few exceptions, most new anticancer agents are initially developed for intravenous use, oral treatment with anticancer agents is, if feasible, to be preferred, as this route of administration is convenient to patients, reduces administration costs and facilitates the use of more chronic treatment regimens. Recent studies have identified various physiological barriers limiting the oral absorption of anticancer drugs. Presently, several strategies are explored to alter the low and variable oral bioavailability of several important anticancer agents by taking advantage of an intentional interaction between anticancer agents and drugs that modulate active intestinal drug transporters or (intestinal) enzymes.

Clinical relevance of biologic factors in male breast cancer.

There is ample information on the clinical role of biologic factors in female breast cancer: urokinase-type plasminogen activator (uPA), its receptor uPAR, its inhibitors PAI-1 and PAI-2, cathepsin D and pS2-protein. However such reports are missing or very rare for male breast cancer. We determined the cytosolic levels of oestrogen receptor (ER), progesterone receptor (PgR), cathepsin D, pS2-protein, uPA, uPAR, PAI-1 and PAI-2 of the primary tumour tissues from 40 male breast cancer patients.

Combination chemotherapy of the taxanes and antimetabolites: its use and limitations.

In an effort to improve response rates of chemotherapy, taxanes have been combined with other cytotoxic agents such as antimetabolites. However, the use of some of these combinations in patients has been restricted by severe toxicity. The significance of the sequence of drug administration in combining methotrexate (MTX) and taxanes was recognised in in vitro studies, showing synergistic effects for the sequence of MTX followed by paclitaxel, and antagonism for exposure in the reverse order.

Dose and schedule-finding study of oral topotecan and weekly cisplatin in patients with recurrent ovarian cancer.

Both weekly cisplatin chemotherapy and single agent topotecan have proven to be effective in recurrent ovarian cancer. Preclinical data show synergism between cisplatin and topotecan. Side effects for this combination are drug sequence dependent and predominantly haematologic.

The (ir)relevance of plasma protein binding of anticancer drugs.

The major purpose of therapeutic drug monitoring is to enable drug dosage individualization for differences among patients in rates of drug metabolism and/or excretion. The standard analytical methods for measuring concentrations of drugs in plasma determine drug bound to plasma proteins as well as free drug dissolved in plasma water. For this reason, the relationship between total drug concentration in plasma and treatment outcome (i.

Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure.

Purpose: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population.

Patients And Methods: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel.

Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation.

Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy.