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Biomedical subjects

A A Gabizon

Publications and source records attributed to A A Gabizon.

8 recordsLinked to original sources
PubMed2001

Pegylated liposomal doxorubicin: metamorphosis of an old drug into a new form of chemotherapy.

Pegylated liposomal doxorubicin (Doxil, Caelyx) is a formulation of doxorubicin in poly(ethylene glycol)-coated (stealth) liposomes with a prolonged circulation time and unique toxicity profile. We review the preclinical and clinical pharmacology as well as recent clinical data obtained in specific cancer types. Doxil liposomes retain the drug payload during circulation and accumulate preferentially in tissues with increased microvascular permeability, as often is the case of tumors. Doxil toxicity profile is drastically different from that of doxorubicin, and is characterized by dominant and dose-limiting mucocutaneous toxicities, mild myelosuppression, minimal alopecia, and no apparent cardiac toxicity. Although the single maximum tolerated dose (MTD) of Doxil is actually lower than that of conventionally administered doxorubicin, the cumulative MTD dose of Doxil may be substantially greater than that of free doxorubicin. Doxil is probably one of the most active agents in AIDS-related Kaposi's sarcoma and has a definite role in management of recurrent ovarian cancer. The potential of Doxil in the treatment of other cancer types and the opportunities it offers in combination with other drugs and therapeutic modalities are under active investigation.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Phase I study of doxil-cisplatin combination chemotherapy in patients with advanced malignancies.

PURPOSE: Our first objective was to evaluate the feasibility of administering a combination of Doxil, a pegylated liposome formulation of doxorubicin, and cisplatin and to determine the maximum tolerated dose of the combination. A secondary objective was to examine Doxil peak and 7-day postinjection plasma levels at the various dose levels tested. METHODS: Patients with advanced solid tumors were treated every 4 weeks with cisplatin on day 1 and Doxil on day 2. In the first three dose levels, the dose of Doxil was fixed at 40 mg/m(2), whereas the dose of cisplatin was escalated from 40 to 50 and 60 mg/m(2). At the fourth and fifth dose levels, the dose of cisplatin was fixed at 60 mg/m(2), whereas the dose of Doxil was escalated to 50 and to 60 mg/m(2). Plasma Doxil (doxorubicin-equivalent) levels were measured by a high-performance liquid chromatography assay with fluorescence detection at 1 h and 7 days after infusion of Doxil. RESULTS: Twenty-six patients entered the study. Twenty-four patients completed a minimum of 2 courses and were fully assessable for toxicity and efficacy. Eighteen patients had received prior chemotherapy, 11 of them with anthracycline-containing regimens. A total of 177 courses were administered within the study. In 12 patients, cisplatin was discontinued after 1 to 13 courses, and Doxil was continued alone for 1-22 courses. All other patients received both drugs until discontinuation of therapy. The dose-limiting toxicities were neutropenia and mucositis. Grade 4 neutropenia was seen in 3 patients (one with neutropenic fever) at dose levels 4 and 5. Grade 3 mucositis was observed in 4 patients at dose levels 3, 4, and 5. In contrast, the most severe palmar-plantar erythrodysesthesia manifestation was grade 2 seen in 1 patient only. Tumor responses included seven partial responses, of which three were in ovarian cancer patients. In four of seven responders, the time to disease progression exceeded 1 year. Doxil 1-h (C(max) equivalent) levels were assessed in 20 patients. The mean Doxil C(max) (mg/l plasma) increased gradually with dose escalation from 14.7 +/- 1.9 for 40 mg/m(2), to 17.3 +/- 3.0 for 50 mg/m(2), and 23.3 +/- 5.5 for 60 mg/m(2). The 60 mg/m(2) C(max) was similar to data obtained in parallel clinical studies at our institution with single-agent Doxil at 60 mg/m(2). However, the 7-day Doxil postinfusion levels were significantly lower in patients receiving the Doxil-cisplatin combination than in those receiving single-agent Doxil. CONCLUSION: Doxil can be administered at full maximum tolerated dose (50 mg/m(2) every 4 weeks) in combination with 60 mg/m(2) cisplatin, with no evidence of major overlapping toxicities. Palmar-plantar erythrodysesthesia incidence and severity appears to be diminished, in comparison with data available for single-agent Doxil. Plasma concentration data point to an accelerated clearance of Doxil when administered after cisplatin.

Adult↗
PubMed1995

Reduction of the systemic toxicity of cisplatin by intra-arterial hepatic route administration for liver malignancies.

Cisplatin (CDDP) administration by the intra-arterial hepatic route (i.a.h.) in patients with primary or metastatic liver malignancies could enhance the anti-tumor activity of the drug and reduce its systemic toxicity. The aim of the present study was to compare Pt pharmacokinetics and the toxicity of the circulating drug after i.a.h. versus intravenous (i.v.) administration. CDDP pharmacokinetics was followed-up in 11 i.a.h. courses given to 7 patients with liver malignancies and compared with 19 i.v. courses in 15 patients with cancer of different origins. The Pt level in blood was monitored by sensitive atomic absorption spectrometry. The dose given was in the range of 25-80 mg/m2/treatment. For analysis and for comparison purposes, the data from both CDDP treatments were normalized to a standard dose of 35 mg/m2. The mean peak Pt level for i.a.h. treatment was found to be about half of the mean peak value for i.v. administration with a similar dose-independent bi-exponential rate of elimination i.a.h. CDDP treatment was relatively well tolerated with no symptoms of either nephro- or neurotoxicity. For in vitro evaluation of peripheral CDDP toxicity, a sensitive ovarian carcinoma cell line, OV-1063, was used. A cytotoxic effect was recorded only within 2 hr following high-dose i.v. CDDP treatment. A substantial fraction of the drug given by the i.a.h. route was found to be extracted by the liver in the first passage, with reduced drug level in the peripheral blood plasma relative to the dose given. This may explain the apparent diminution of side-effects following i.a.h. CDDP treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Liposomal anthracyclines.

Preclinical experiments with liposome-encapsulated anthracyclines indicate that this form of delivery may be effective in decreasing the cardiotoxic effect of these drugs. The tumor drug levels and the antitumor efficacy of anthracyclines in a number of mouse models are significantly enhanced by delivery in long-circulating liposomes. Drastic changes in the clinical pharmacokinetics of doxorubicin have been observed using liposomal delivery. Clinical trials with liposomal anthracycline preparations are ongoing to determine whether the pharmacokinetic changes are translated in a superior therapeutic index of this important group of chemotherapeutic agents.

Animals↗
PubMed1993

Prolongation of the circulation time of doxorubicin encapsulated in liposomes containing a polyethylene glycol-derivatized phospholipid: pharmacokinetic studies in rodents and dogs.

The pharmacokinetics of doxorubicin (DOX) encapsulated in liposomes containing polyethylene glycol-derivatized distearoylphosphatidylethanolamine (PEG/DSPE) were investigated in rodents and dogs. The plasma levels of DOX obtained with PEG/DSPE-containing liposomes were consistently higher than those without PEG/DSPE or when PEG/DSPE was replaced with hydrogenated phosphatidylinositol (HPI). Despite the inclusion of PEG/DSPE in liposomes, there was a significant drop in the plasma levels of DOX when the main phospholipid component, hydrogenated phosphatidylcholine, was replaced with lipids of lower phase transition temperature (dipalmitoylphosphatidylcholine, egg phosphatidylcholine), indicating that phase transition temperature affects the pharmacokinetics of liposome-encapsulated DOX. In beagle dogs, clearance was significantly slower for DOX encapsulated in PEG/DSPE-containing liposomes than in HPI-containing liposomes, with distribution half-lives of 29 and 13 hr, respectively. In both instances, almost 100% of the drug measured in plasma was liposome-associated. The apparent volume of distribution was only slightly above the estimated plasma volume of the dogs, indicating that drug leakage from circulating liposomes is insignificant and that the distribution of liposomal drug is limited mostly to the intravascular compartment in healthy animals.

Animals↗
PubMed1992

In vitro cytotoxicity of liposome-encapsulated doxorubicin: dependence on liposome composition and drug release.

We have investigated the in vitro cytotoxicity of free doxorubicin (DOX) and liposome-entrapped DOX (L-DOX) against a human ovarian carcinoma cell line (OV-1063) using a colorimetric assay. DOX was encapsulated in the inner water phase of liposomes by an ammonium sulfate-generated proton gradient. Liposomes varied in phospholipid composition but were of a similar size. It was found that the cytotoxic activity of L-DOX is substantially decreased when liposomes containing phospholipids of high phase-transition temperature (Tm) are used. The type of negatively charged headgroup did not have any significant influence on the cytotoxicity observed. Experiments using resin beads that bind free and protein-bound DOX, but do not interact with L-DOX, indicated that the cytotoxic effect is mediated by the release of drug from the liposomes into the extracellular medium; no evidence was found for direct cellular uptake of liposome-encapsulated drug. The use of the ionophore nigericin to induce the release of DOX from high-Tm liposomes increased cytotoxicity to a level comparable to free DOX, suggesting that 'remote release' techniques may substantially improve the efficiency of liposome-mediated drug delivery and allow for the full exploitation of the favorable pharmacokinetic properties of specific high-Tm formulations.

Cell Division↗
PubMed1992

Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes.

We have investigated the tissue distribution, toxicity, and antitumor activity of anthracyclines encapsulated in hydrogenated phosphatidylinositol (HPI)-containing liposomes which show a characteristic long circulation time in plasma (J. Natl. Cancer Inst., 81: 1484-1488, 1989). Phosphatidylglycerol (PG)-containing liposomes were used for comparison. Doxorubicin (DOX) or epirubicin (EPI) was encapsulated in the aqueous interior of small (65-100 nm mean diameter) HPI or PG liposomes. The DOX and EPI levels in i.m. tumor implants of the J6456 lymphoma were significantly raised by delivery in HPI liposomes but not by delivery in PG liposomes. No such increase was observed in normal muscle tissue. When DOX encapsulated in HPI liposomes was injected i.v. into BALB/c mice bearing an ascitic form of the J6456 lymphoma, more than 10% of the injected dose was recovered in the ascitic fluid in liposome-associated form. No significant accumulation of liposomal drug was observed in peritoneal washes from tumor-free mice. DOX encapsulation in either PG- or HPI-containing liposomes reduced the lethal toxicity of the drug in mice. However, only the HPI-DOX formulation was significantly more active than free DOX in the treatment of the ascitic J6456 tumor at all dose levels tested. Therapeutic results with EPI encapsulated in HPI liposomes also showed an efficacy superior to that of free EPI. These studies provide evidence that anthracyclines delivered in long-circulating liposomes extravasate with relative selectivity in tumor areas, improving the overall therapeutic index.

Animals↗