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9. Reversal of multidrug resistance in human colon cancer cells expressing the human MDR1 gene by liposomes in combination with monoclonal antibody or verapamil

Author

Sela, Shifra, Husain, Syed R., Pearson, John W., Longo, Dan L., and Rahman, Aquilur

Subjects
Drug resistance -- Prevention, Monoclonal antibodies -- Usage, Verapamil -- Usage, Health
Abstract

Colorectal cancer is a major cause of cancer-related mortality in the world and the second leading cause of neoplastic death in the United States. A major obstacle in the chemotherapy of this neoplasm is the emergence of mulidrug resistance that is frequently associated with the expression of P-glycoprotein (p170) encoded by MDR1 (also known as PGY1) genes. Previously, we demonstrated that liposome-encapsulated doxorubicin is more cytotoxic than free doxorubicin in human promyelocytic leukemia and human breast cancer cells with the multidrug-resistant phenotype. Purpose: Our purpose was to investigate modulation of multidrug resistance by liposome-encapsulated vincristine (VCR) in a drug-resistant human colon cancer cell line HT-[29.sup.mdr1] and the potentiation of this modulation in combination with monoclonal antibody MRK-16 or verapamil. Methods: HT-29 parental cells and HT-[29.sup.mdr1] cells were exposed to free VCR or liposome-encapsulated VCR alone or in combination with MRK-16 or verapamil. Cytotoxicity of cells after various treatments was determined by neutral red staining, and cellular content of VCR was measured by using radiolabeled VCR; p170 expression of cells was assessed by azidopine. Results: HT-[29.sup.mdr1] cells express a high amount of p170, thus conferring sixfold to sevenfold resistance to VCR compared with the parent cell line. Liposone-encapsulated VCR lowers drug resistance in HT-[29.sup.mdr1] cells fourfold; I[C.sub.50] values (concentration that causes 50% reduction in cell number) were 12.5 [+ or -] 2.5 ng/mL compared with 42.5 [+ or -] 5.0 ng/mL with free VCR. I[C.sub.50] values for free VCR with empty liposomes were 25 [+ or -] 1.25 ng/mL. The combination of MRK-16 and free VCR produced a twofold increase in cytotoxicity over free VCR in p170-expressing cells; the combination of MRK-16 and liposome-encapsulated VCR produced a 10-fold potentiation of cytotoxicity. Nonspecific monoclonal antibody NR-LU-10 had no effect on cytotoxicity of HT-[29.sup.mdr1] cells with free VCR or liposome-encapsulated VCR. The combination of 1.5 [micro]M verapamil potentiated the cytotoxicity of free VCR ninefold to 10-fold, I[C.sub.50] values reduced to 5.0 [+ or -] 1.5 ng/mL, and in combination with liposome-encapsulated VCR, I[C.sub.50] values reduced to 2.5 [+ or -] 1.0 ng/mL, demonstrating a 15- to 17-fold potentiation of cytotoxicity. There were no significant differences in drug accumulation in HT-[29.sup.mdr1] cells when treated with liposome-encapsulated VCR or free VCR. Liposomes inhibited the photoaffinity labeling of azidopine to p170 HT-[29.sup.mdr1] cells. Conclusions: Liposome encapsulation of VCR effectively modulates multidrug resistance in human colon cancer cells and may become an important modality in treatment for colon cancers.

Published
1995

10. Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells

Author

Rahman, Aquilur, Husain, Syed R., Siddiqui, Javed, Verma, Madhu, Agresti, Michael, Center, Melvin, Safa, Ahmad R., and Glazer, Robert I.

Subjects
Drug resistance -- Research, Doxorubicin -- Dosage and administration, Liposomes -- Health aspects, Drugs -- Vehicles, Health
Abstract

Background: Multidrug resistance (MDR) is a major obstacle in cancer treatment. Resistance of cultured tumor cells to major classes of cytotoxic drugs is frequently due to expression of a plasma membrane P-glycoprotein encoded by MDR genes. We have demonstrated that liposome-encapsulated doxorubicin is more toxic than the free drug and that it modulates MDR in Chinese hamster LZ cells and human colon cancer cells. Purpose: To investigate further the association between expression of P-glycoprotein and modulation of MDR by liposome-encapsulated doxorubicin, we studied vincristine-resistant HL-60/VCR leukemia cells, which express P-glycoprotein, and doxorubicin-resistant HL-60/ADR leukemia cells, which do not. Methods: Cells were exposed to various concentrations of free doxorubicin and liposome-encapsulated doxorubicin. The cellular content of doxorubicin was determined by fluorescence analysis, and cytotoxicity was determined by cell growth inhibition. Photoaffinity-labeling studies of P-glycoprotein binding were performed on HL-60/VCR and HL-60/ADR cells and KB-GSV2 cells transfected with the MDR1 gene (also known as PGY1). Results: The concentrations that caused 50% inhibition of growth ([IC.sub.50]) for free doxorubicin in HL-60, HL-60/ADR, and HL-60/VCR cells were 30 nM, 9 [Mu]M, and 0.9 [Mu]M, respectively. The values for liposome-encapsulated doxorubicin in parental HL-60 cells and HL-60/ADR cells were 20 nM and 9 [Mu], respectively, indicating little or no sensitization. In contrast, HL-60/ VCR cells were fivefold more sensitive to liposome-encapsulated doxorubicin, and [IC.sub.50] was reduced to 0.17 [Mu]M. In HL-60 cells exposed to liposome-encapsulated doxorubicin, intracellular doxorubicin accumulation was less than that seen with free drug. In contrast, in HL-60/VCR cells, accumulations was twofold to threefold higher than that with free doxorubicin. Liposome-encapsulated doxorubicin completely inhibited the photoaffinity labeling of P-glycoprotein by azidopine in membrane vesicles of HL-60/VCR cells, with a potency comparable to that of azidopine, suggesting that circumvention of MDR by liposomes is related to their specific interaction with P-glycoprotein. The studies with KB-GSV2 cells indicated that blank liposome can directly inhibit photoaffinity labeling of P-glycoprotein. Conclusions: These results demonstrate the effectiveness of liposome-encapsulated doxorubicin in overcoming resistance in the multidrug-resistant phenotype of HL-60/VCR cells by direct interaction with P-glycoprotein. Furthermore, they indicate that liposome-encapsulated doxorubicin may be an effective treatment for human cancers. [J Natl Cancer Inst 84:1909-1915, 1992]

Published
1992

16. A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies

Author

Deeken, John F., primary, Slack, Rebecca, additional, Weiss, Glen J., additional, Ramanathan, Ramesh K., additional, Pishvaian, Michael J., additional, Hwang, Jimmy, additional, Lewandowski, Karen, additional, Subramaniam, Deepa, additional, He, Aiwu Ruth, additional, Cotarla, Ion, additional, Rahman, Aquilur, additional, and Marshall, John L., additional

Published
2012
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35. Antitumor Activity of Liposome-Encapsulated Doxorubicin in Advanced Breast Cancer: Phase II Study.

Author

Treat, Joseph, Greenspan, Andrew, Forst, Diana, Sanchez, Julian A., Ferrans, Victor J., Potkul, Laurel A., Woolley, Paul V., and Rahman, Aquilur

Abstract

Previous studies in animals have demonstrated liposome-encapsulated doxorubicin (LED) has substantially less cardiac toxicity than free doxorubicin but retains antitumor activity. In a phase I clinical study of LED, the maximum tolerated dose was 90 mg/mand dose-limiting toxicity was considered to have been reached when granulocytopenia was produced. We used LED to treat 20 patients with advanced, measurable breast cancer. LED was given at doses of 60–75 mg/m every 3 weeks as an intravenous infusion. Regression of disease was objectively measured in nine patients; in five of these patients, complete regression of the index lesion occurred. The mean duration of the responses was 7 months. Hematologic toxicity consisted of grade 1–2 leukopenia in some patients. Gastrointestinal toxicity and mucositis were generally mild and tolerable. Alopecia occurred in all patients and usually was complete. Twelve patients received cumulative doses of LED of greater than 400 mg/m and were evaluated with radionuclide ventriculograms. In eight patients, the cumulative dose was greater than 500 mg/m, and five had endomyocardial biopsies. Four of these biopsy results were Billingham grade 0, while one (cumulative LED dose, 750 mg/m) showed grade 1 changes with mild myofibrillar loss and dilatation of the sarcoplasmic reticulum involving less than 5% of cardiac myocytes. Two patients had decreases in left ventricular ejection fraction. One of these patients had received a total dose of LED of 630 mg/m and had a decline of 13% in left ventricular ejection fraction, but had no clinical evidence of congestive heart failure and had a Billingham grade 0 endomyocardial biopsy. A second patient, who received a total dose of LED of 660 mg/m plus a 300-mg/m dose of free doxorubicin as adjuvant therapy more than a year prior to beginning LED treatment, had a decline of 17% in ejection fraction and developed congestive heart failure. An endomyocardial biopsy performed after failure developed showed Billingham grade 0 changes. These data show that LED has anti-tumor activity in patients with breast cancer and suggest that it is less cardio-toxic than free doxorubicin at cumulative doses of 500–880 mg/m. [J Natl Cancer Inst 82: 1706–1710, 1990] [ABSTRACT FROM PUBLISHER]

Published
1990

36. Anti-Laminin Receptor Antibody Targeting of Liposomes With Encapsulated Doxorubicin to Human Breast Cancer Cells In Vitro.

Author

Rahman, Aquilur, Panneerselvam, M., Guirguis, R., Castronovo, V., Sobel, Mark E., Abraham, K., Daddona, Peter E., and Liotta, Lance A.

Abstract

The tumor cell laminin receptor is a cell-surface protein that binds laminin with high affinity (K = 1.0 n). The putative ligand-binding domain of the laminin receptor has been molecularly cloned and sequenced. In the present study, we used the predicted amino acid sequence of the laminin receptor to generate synthetic peptide antigens and produced immunoglobulin M (IgM) anti-laminin receptor monoclonal antibodies. The disulfide bond group of the IgM molecule was used to couple the antibodies to the surface of liposomes encapsulating doxorubicin. The anti-laminin receptor monoclonal antibodies coupled to the liposomes bound avidly to the surface of MDA-MB-435S (MDA-435) human breast carcinoma cells, which have high numbers of laminin receptors. These antibody-coupled liposomes exhibited a low degree of binding to Hs 578Bst (Hs 578) normal human breast epithelial cells, which express a low number of laminin receptors. Excess liposomes competed for the binding of unbound laminin to the tumor cell surface, and excess laminin competed for binding with the liposomes. Antibody-coupled liposomes encapsulating doxorubicin were specifically more efficient in inhibiting colony formation by MDA-435 cells in vitro than unbound doxorubicin or liposomes without anti-laminin receptor monoclonal antibodies. Unbound doxorubicin inhibited thymidine uptake by 10%–20% in both Hs 578 and MDA-435 cells, whereas the antibody-coupled liposomes encapsulating doxorubicin inhibited thymidine uptake by 90% in MDA-435 cells but only 15% in Hs 578 cells. Thus, use of anti-laminin receptor monoclonal antibodies coupled with liposomes encapsulating doxorubicin represents a new strategy for selective targeting of doxorubicin to carcinoma cells with exposed laminin receptors. [J Natl Cancer Inst 81:1794–1800, 1989] [ABSTRACT FROM PUBLISHER]

Published
1989

37. Dissolution and Absorption of the Antineoplastic Agent Ellipticine

Author

Rahman, Aquilur, Cradock, James C., and Paul Davignon, J.

Abstract

Ellipticine, a poorly water-soluble alkaloid, is active in several experimental tumor systems. Marked solubility increases were produced by polyvinylpyrrolidone of varying molecular weights (10,000–160,000) and were optimal (~13mg/ml at 25°) with polyvinylpyrrolidone mol. wt. 10,000. Dissolution of ellipticine-polyvinylpyrro-lidone (1:22 w/w) tablets in simulated gastric juice was superior to that of ellipticine hydrochloride. Release rates were controlled by combinations of polyvinylpyrrolidone polymers without affecting maximum dissolution at 37°. Physiological disposition of ellipticine-polyvinyl- pyrrolidone was compared with that of the hydrochloride salt and ellipticine in suspension following oral administration at 250mg/kg in fasted mice. In comparison to the suspension, ellipticine tissue levels were about threefold higher with polyvinylpyrrolidone or hydrochloride preparations. Antitumor activity of the three preparations was evaluated intraperito-neally and orally versusL-1210 leukemia. The optimal dose of ellipticine-polyvinylpyrrolidone and ellipticine hydrochloride was lower than that of the suspension and suggested improved absorption.

Published
1978
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45. Pharmacokinetics, toxicity, and efficacy of ends-modified raf antisense oligodeoxyribonucleotide encapsulated in a novel cationic liposome.

Author

Gokhale PC, Zhang C, Newsome JT, Pei J, Ahmad I, Rahman A, Dritschilo A, and Kasid UN

Subjects
Animals, Cations, Cell Division, Cell Survival, Female, Humans, Macaca fascicularis, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Prostatic Neoplasms drug therapy, Proto-Oncogene Proteins c-raf metabolism, Rabbits, Temperature, Time Factors, Tumor Cells, Cultured, Liposomes metabolism, Oligonucleotides, Antisense pharmacokinetics, Proto-Oncogene Proteins c-raf genetics
Abstract

Raf-1 protein serine threonine kinase plays an important role in cell survival and proliferation. Antisense inhibition of Raf-1 expression has been shown to enhance the cytotoxic effects of radiation and anticancer drugs. Here we have evaluated the toxicity, pharmacokinetics, and antitumor efficacy of a novel formulation of liposome-entrapped raf antisense oligodeoxyribonucleotide (LErafAON). The LErafAON preparation showed high liposome entrapment efficiency of rafAON (>85%) and stability at room temperature. In CD2F1 mice, administration of LErafAON produced no morbidity/mortality (5-35 mg/kg/dose, i.v., x12). Dose-related elevations in liver enzymes (alanine aminotransferase and aspartate aminotransferase) and histopathological changes in liver were noted in LErafAON and blank liposome groups. No morbidity/mortality and changes in clinical chemistry or histopathology were observed in New Zealand white rabbits (3.75 mg/kg/dose, i.v., x8; 6.5 mg/kg/dose, i.v., x6) or in cynomolgous monkeys (3.75 or 6.25 mg/kg/dose, i.v., x9). Transient decrease in total hemolytic complement activity (approximately 62-74%) and increases in C3a (approximately 3-fold) and Bb levels (approximately 5-12-fold) were observed in LErafAON and blank liposome groups of monkeys. A 30 mg/kg i.v. dose of LErafAON in human prostate tumor (PC-3)-bearing BALB/c athymic mice gave a terminal plasma half-life of 27 h, and intact rafAON could be detected in plasma and in normal and tumor tissues for up to at least 48 h. In monkeys, the terminal plasma half-life of 30.36 +/- 23.87 h was observed at an i.v. dose of 6.25 mg/kg. LErafAON (25 mg/kg/dose, i.v., x10) or ionizing radiation (3.8 Gy/day, x5) treatment of PC-3 tumor-bearing athymic mice led to tumor growth arrest, whereas a combination of LErafAON and ionizing radiation treatments resulted in tumor regression. LErafAON treatment caused inhibition of Raf-1 protein expression in normal and tumor tissues in these mice (>50%, versus controls). These data have formed a basis of the clinical Phase I studies of LErafAON for cancer treatment.

Published
2002

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