Maria O. Vannozzi

Pleural space perfusion with cisplatin in the multimodality treatment of malignant mesothelioma: A feasibility and pharmacokinetic study

INTRODUCTION Malignant pleural mesothelioma is an ideal model for testing new locoregional multimodality approaches because of its aggressive local behavior. METHODS This study was planned to investigate the feasibility, safety, and pharmacokinetics of a multimodality therapy including an operation, pleural space perfusion (60 minutes) with cisplatin (100 mg/m2), hyperthermia (41. 5 degrees C), and postoperative radiotherapy (55 Gy to chest wall incisions). The effects of the extent of resection and perfusion temperature on cisplatin pharmacokinetics were evaluated. Ten patients with epithelial or mixed, stage I or II, malignant pleural mesothelioma underwent the following procedures: group A (3 patients), pleurectomy/decortication and normothermic pleural space antineoplastic perfusion; group B (3 patients), pleurectomy/decortication and hyperthermic perfusion; and group C (4 patients), pleuropneumonectomy and hyperthermic perfusion. Operations were selectively applied depending on tumor extent. Platinum levels were serially measured by atomic absorption in systemic blood, perfusate, lung, and endothoracic fascia. RESULTS The overall procedure was completed in every case, without any death or toxicity. No lung damage was demonstrated after treatment. Major complications included 1 wound infection and 1 diaphragmatic prosthesis displacement. The mean peak platinum plasma levels were reached within 45 to 60 minutes after perfusion was started. Systemic drug concentrations were greater after pleurectomy/decortication than after pleuropneumonectomy (P =.006). The local tissue/perfusate ratio of platinum concentrations tended to be higher after hyperthermic perfusion rather than normothermic perfusion. CONCLUSION This multimodality approach is feasible, pharmacokinetically advantageous, and safe enough to undergo further clinical investigations.

Isolated lung perfusion with platinum in the treatment of pulmonary metastases from soft tissue sarcomas

A multimodality approach including operation and isolated lung perfusion with platinum was used in six patients with lung metastases from soft tissue sarcomas. Staged thoracotomies were used in two patients with bilateral lesions. The inclusion criteria generally applied for surgical excision were adopted in this study. The pulmonary artery and a portion of the left atrium were isolated from systemic circulation and cannulated. The cannulas were then connected to a perfusion circuit and normothermic isolated lung perfusion was done for 60 minutes. The lung was then flushed and metastasectomy was done. Serial blood (systemic and pulmonary), tissue (normal lung and tumor), and urine samples were obtained for platinum content measurement by flameless atomic absorption spectroscopy. Lung damage was assessed by light and electron microscopy examination and by serial respiratory tests. Isolated lung perfusion was accomplished in all patients without any death, operative complication, or systemic toxicity. After operation, interstitial and alveolar edema developed in two patients (48 hours after treatment), necessitating respiratory support in one case. Total platinum concentrations in pulmonary plasma were about 43 times greater than those in systemic plasma. No differences in platinum concentrations between normal lung and metastatic tissue were found. Thus the proposed isolated lung perfusion technique is feasible and safe enough to be offered as a valid model to study combined chemosurgical approaches in the treatment of lung metastases.

Reduction of cisplatin hepatotoxicity by procainamide hydrochloride in rats

In preceding papers, we proposed that procainamide hydrochloride, a class I antiarrhythmic agent, was able to protect mice and rats from cisplatin-induced nephrotoxicity and that it could exert its action through accumulation in kidneys followed by coordination with cisplatin (or its hydrolysis metabolites) and formation of a less toxic platinum compound similar to the new platinum(II) triamine complex cis-diamminechloro-[2-(diethylamino)ethyl 4-amino-benzoate, N4]-chlorideplatinum(II) monohydrochloride monohydrate, obtained by the reaction of cisplatin with procaine hydrochloride. Hepatotoxicity is not considered as a dose-limiting toxicity for cisplatin, but liver toxicity can occur when the antineoplastic drug is administered at high doses. Here, we report that procainamide hydrochloride, at an i.p. dose of 100 mg/kg, reduces cisplatin-induced hepatotoxicity, as evidenced by the normalization of plasma activity of glutamic oxalacetic transaminase and gamma-glutamyl transpeptidase, as well as by histological examination of the liver tissue. Twenty-four hours after i.p. treatment with the combination of 7.5 mg/kg cisplatin and 100 mg/kg procainamide, a significant increase of procainamide (+56%, P<0.05), total platinum (+31%, P<0.05), platinum-DNA adducts (+31%, P<0.05) and percent DNA-DNA interstrand cross-links (+69%, P<0.02) was found in liver tissue, as compared to animals treated with cisplatin alone. Moreover, in accordance with these findings, we also observed a slightly lower concentration and cumulative excretion of platinum in the feces. Since mitochondrial injury is considered a central event in the early stages of the nephrotoxic effect of cisplatin, the distribution of platinum in these subcellular organelles obtained from hepatocytes was determined after treatment with cisplatin with or without procainamide hydrochloride, together with platinum concentration in their cytosolic fraction. Our data show that the coadministration of procainamide hydrochloride produced a rearrangement of subcellular platinum distribution in hepatocytes with a slight decrease in mitochondria (-15%, P<0.10) and a slight increase in the cytosolic fraction (+40%, P<0.10) of platinum content, compared to the treatment with cisplatin alone. In analogy with our previous results in the kidney, confirmed here by our data in vitro, we suggest that the hepatoprotective activity of procainamide hydrochloride is linked to the formation of a less toxic platinum complex, which leads to inactivation of cisplatin itself and/or its highly toxic hydrolysis metabolites and to a different subcellular distribution of platinum.

Comparative Effects of Paclitaxel and Docetaxel on the Metabolism and Pharmacokinetics of Epirubicin in Breast Cancer Patients

PURPOSE To investigate whether paclitaxel and docetaxel influence the pharmacokinetics and metabolism of epirubicin. PATIENTS AND METHODS We studied the pharmacokinetics and biotransformation patterns of epirubicin in 27 cycles and 20 breast cancer patients. Four patients received epirubicin alone 90 mg/m(2) by intravenous (IV) bolus; eight patients received the same dose of epirubicin followed immediately by paclitaxel 175 mg/m(2) in a 3-hour infusion; the other eight patients received epirubicin 90 mg/m(2) followed immediately by docetaxel 70 mg/m(2) in a 1-hour infusion. Epirubicin and its metabolites, epirubicinol (EOL) and 7-deoxydoxorubicinone (7d-Aone), were identified by high-pressure liquid chromatography. RESULTS No pharmacokinetic interaction between the parent compound epirubicin and taxanes was detected. Conversely, a significant effect on epirubicin metabolism by both paclitaxel and docetaxel was found. Epirubicin given with paclitaxel or docetaxel yielded areas under the plasma concentration-time curves (AUC) for 7d-Aone 1. 7-fold and 1.9-fold higher (P <.05), respectively, than epirubicin alone. The appearance of two polar metabolites sensitive to glucuronidase was also significantly greater in both taxane groups. Quantitatively different metabolic rates and patterns for EOL were observed in the paclitaxel and docetaxel combinations. The EOL AUC after paclitaxel treatment (1,521 +/- 150 ng/mL*h) was significantly higher (P <.01) than the corresponding values after epirubicin administered either as a single agent (692 +/- 46 ng/mL*h) or in combination with docetaxel (848 +/- 237 ng/mL*h). CONCLUSION There is no apparent pharmacokinetic interaction between the parent compound epirubicin and paclitaxel or docetaxel. A different pattern of interaction between these taxanes and epirubicin metabolism is clearly evident.

Sequence Effect of Epirubicin and Paclitaxel Treatment on Pharmacokinetics and Toxicity

PURPOSE Sequence-dependent clinical and pharmacokinetic interactions between paclitaxel and doxorubicin have been reported. Some data have shown an influence of paclitaxel on epirubicin metabolism, but no data are available about the effect of diverse sequences of these drugs. We investigated whether reversing the sequence of epirubicin and paclitaxel affects the pattern or degree of toxicity and pharmacokinetics. PATIENTS AND METHODS Patients receiving epirubicin 90 mg/m(2) by intravenous bolus followed by paclitaxel 175 mg/m(2) over 3-hour infusion or the opposite sequence every 3 weeks for four cycles were eligible. Toxicity was recorded at nadir. Pharmacokinetic data were evaluated at the first and the second cycle and were correlated with toxicity parameters. RESULTS Thirty-nine consecutive stage II breast cancer patients were treated. Twenty-one patients received epirubicin followed by paclitaxel (ET group), and 18 received the opposite sequence (TE group). No significant difference in nonhematologic toxicity was seen. A lower neutrophil and platelet nadir and a statistically significant slower neutrophil recovery was observed in the TE group. Area under the concentration-time curve (AUC) of epirubicin was higher in the TE group (2,346 ng/mL. h v 1,717 ng/mL. h; P =.002). An inverse linear correlation between epirubicin AUC and neutrophil recovery was also observed (P =.012). No difference was detected in paclitaxel pharmacokinetics. CONCLUSION Our results support a sequence-dependent effect of paclitaxel over epirubicin pharmacokinetics that is associated with increased myelotoxicity. Because schedule modifications of anthracyclines and paclitaxel can have clinical consequences, the classical way of administration (ie, anthracyclines followed by paclitaxel) should be maintained in clinical practice.

Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases.

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with and without coadministration of 600 mg degradable starch microspheres (DSM). Mean (± standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 ± 0.69 μg/ml) than after DDP alone (2.13 ± 0.43 μg/ml, P less than 0.05), with the area under the curve (AUC10–30 min) values of 15.8 ± 5.5 and 25.1 ± 3.8 μg × min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 ± 1.60 μg/g) than after DDP alone (0.67 ± 0.49 μg/ml, P less than 0.05). Liver concentrations and tumor‐liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole‐liver extraction of the drug and a redistribution of blood flow and flow‐dependent tissue uptake of platinum.

Regional pharmacokinetic selectivity of intrapleural cisplatin

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

High doses of intrapleural cisplatin in a case of malignant pleural mesothelioma : clinical observations and pharmacokinetic analyses

Background. The authors report a feasibility study of intrapleural cisplatin in a patient with inoperable malignant pleural mesothelioma.

Suramin/epidoxorubicin association in hormone-refractory prostate cancer: preliminary results of a pilot phase II study

Purpose: Previous studies indicate that suramin may be an active agent for treating hormone-retractory prostate cancer. However, antitumour responses were observed in initial experiments only when plasma suramin concentrations were maintanined in excess of 250 μg/ml. Dose-limiting toxicity, especially neurological toxicity, is directly related to the duration of exposure and sustained plasma drug concentrations of 300 μg/ml or more. Combination with other agents such as epidoxorubicin, a drug with demonstrable activity in metastatic prostatic carcinoma, could be more effective and allow reduced suramin doses, while maintaining the suramin antitumor effect; this could make suramin therapy more feasible. On the basis of preclinical synergistic activity for combined suramin/doxorubicin in prostate cancer cell lines, a pilot study in patients with metastatic hormone refractory prostate cancer was performed.Materials and methods: Ten patients with hormone-refractory prostate cancer received a fixed dosing scheme of suramin infusion in combination with weekly epidoxorubicin at 25 mg/m2. Therapy was discontinued for dose-limiting toxicity or progressive disease.Results: None of the ten patients achieved a prostate-specific antigen reduction of more than 50% and no objective responses were observed in any patient. Dose-limiting toxicity was observed in four patients: grade 3 neurotoxicity was observed in three patients and grade 3 nephrotoxicity in one patient.Conclusions: Suramin/epidoxorubicin association, despite the encouraging preclinical results, was not able to improve the antitumour activity of suramin and showed significant toxicity. The results achieved in our study, although in a small number of patients, seem to suggest that this regimen cannot be recommended for use in the treatment of metastatic hormone-refractory prostate cancer.

Inhibition of Cell Growth, Induction of Apoptosis and Mechanism of Action of the Novel Platinum Compound cis-Diaminechloro-[2-(Diethylamino) Ethyl 4-Amino-Benzoate, N4]-Chloride Platinum (II) Monohydrochloride Monohydrate

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a new platinum triamine complex obtained from the synthesis of cisplatin and procaine. In this paper we analyzed, adopting a disease-oriented strategy, the tumour selectivity of this compound, its ability to induce apoptosis and its mechanism of interaction with DNA. The inhibition of cell proliferation was evaluated by the MTT assay using a panel of 51 tumour cell lines. Some of them were also evaluated for the induction of apoptosis by 4′-6-diamidine-2′-phenylindole (DAPI) staining, Western blot of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, interstand cross-links (ISCL) were evaluated by ethidium bromide fluorescence technique.When evaluated by the MTT assay, DPR showed a high selective activity for neuroblastoma, small cell lung cancer (SCLC), ovarian cancer and leukemia cell lines. The comparison of mean graphs of DPR and cisplatin suggested that our compound possesses a mechanism of action similar to that, at least in part, of its parent compound. Moreover, DPR showed itself to be a good trigger of programmed cell death, as demonstrated by DAPI staining, activation of p53 protein and agarose gel electrophoresis of ladder DNA. Finally, the study of the formation of ISCLs demonstrated that DPR, despite being a monofunctional platinum compound, is able to form bifunctional adducts through the release of procaine residue.Data presented here suggest that DPR is an antitumour agent able to trigger apoptosis, and that it is endowed with a peculiar mechanism(s) of action and a special selective activity against two tumours, namely neuroblastoma and SCLC, which are still characterized by a low incidence of long-term survivors.