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Article ; Online: Clinical overview on Lipoplatin: a successful liposomal formulation of cisplatin.

Boulikas, Teni

2009 Volume 18, Issue 8, Page(s) 1197–1218

Abstract: Nanoparticle formulations for packaging existing drugs have been used to treat cancer. Lipoplatin is a liposomal cisplatin encapsulated into liposome nanoparticles of an average diameter of 110 nm. Lipoplatin has substantially reduced the renal toxicity, ...

Abstract	Nanoparticle formulations for packaging existing drugs have been used to treat cancer. Lipoplatin is a liposomal cisplatin encapsulated into liposome nanoparticles of an average diameter of 110 nm. Lipoplatin has substantially reduced the renal toxicity, peripheral neuropathy, ototoxicity, myelotoxicity as well as nausea/vomiting and asthenia of cisplatin in Phase I, II and III clinical studies with enhanced or similar efficacy to cisplatin. During clinical development, 10- to 200-fold higher accumulation of Lipoplatin in solid tumors compared to adjacent normal tissue was found in patients. Targeting of tumor vasculature by Lipoplatin in animals suggested its antiangiogenesis potential and Lipoplatin was proposed to act like a double-sword: as chemotherapy and an antiangiogenesis drug. Lipoplatin has finished successfully one Phase III non-inferiority clinical study as first-line against NSCLC in its combination with paclitaxel showing statistically significant reduction in nephrotoxicity; two more Phase III studies are in progress, one in NSCLC with gemcitabine also showing noninferiority with reduced toxicity and another in squamous cell carcinoma of the head and neck with 5-fluorouracil. A registrational Phase II/III study against pancreatic cancer is in progress under the orphan drug status granted to Lipoplatin by the European Medicines Agency. Phase II studies are continuing in advanced breast cancer with vinorelbine and gastrointestinal cancers with radiotherapy and 5-fluorouracil. The highlights of the clinical development of Lipoplatin are reviewed.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Cisplatin/administration & dosage ; Cisplatin/adverse effects ; Cisplatin/pharmacokinetics ; Cisplatin/pharmacology ; Cisplatin/therapeutic use ; Clinical Trials as Topic ; Drug Screening Assays, Antitumor ; Humans ; Liposomes ; Molecular Structure ; Nanoparticles ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology
Chemical Substances	Antineoplastic Agents ; Liposomes ; lipoplatin ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2009-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1182884-5
ISSN	1744-7658 ; 0967-8298 ; 1354-3784
ISSN (online)	1744-7658
ISSN	0967-8298 ; 1354-3784
DOI	10.1517/13543780903114168
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Zs.A 3739: Show issues

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Article: Low toxicity and anticancer activity of a novel liposomal cisplatin (Lipoplatin) in mouse xenografts.

Boulikas, Teni

Oncology reports

2004 Volume 12, Issue 1, Page(s) 3–12

Abstract: Cisplatin has been one of the most widely used and most effective cytotoxic agents in the treatment of malignancies but causes severe adverse reactions including nausea/vomiting, renal toxicity, gastrointestinal toxicity, peripheral neuropathy, asthenia, ...

Abstract	Cisplatin has been one of the most widely used and most effective cytotoxic agents in the treatment of malignancies but causes severe adverse reactions including nausea/vomiting, renal toxicity, gastrointestinal toxicity, peripheral neuropathy, asthenia, and ototoxicity. A liposomal formulation of cisplatin, Lipoplatin, was developed in order to reduce the systemic toxicity of cisplatin. A single treatment of rats with 30 mg/kg Lipoplatin resulted in no toxicity whereas 2 or 3 weekly administrations at 30 mg/kg to rats gave neutropenia but no nephrotoxicity. On the contrary, a single injection to rats of 5 mg/kg cisplatin resulted in severe nephrotoxicity. Thus, Lipoplatin is less toxic than cisplatin in rats. Intraperitoneal or intravenous injection of Lipoplatin to SCID (severe combined immunodeficient) mice with subcutaneous breast MCF-7 or prostate LNCaP human tumors resulted in size reduction of the tumors; histological examination of the treated tumors in xenografts was consistent with apoptosis in tumor cells; thus, Lipoplatin appears to exert its cytotoxic effects to tumors in a mechanism similar to that of cisplatin. The preclinical studies reported here set the foundation for the clinical use of Lipoplatin as an exciting new drug with lower toxicity than cisplatin, endowed with proapoptotic properties.
MeSH term(s)	Animals ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cisplatin/pharmacokinetics ; Cisplatin/therapeutic use ; Cisplatin/toxicity ; Drug Carriers ; Female ; Humans ; Liposomes ; Male ; Mice ; Mice, SCID ; Neoplasms/drug therapy ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/pathology ; Rats ; Rats, Wistar ; Transplantation, Heterologous
Chemical Substances	Drug Carriers ; Liposomes ; lipoplatin ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2004-07
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1222484-4
ISSN	1791-2431 ; 1021-335X
ISSN (online)	1791-2431
ISSN	1021-335X
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Zs.A 4213: Show issues

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Article: Recent clinical trials using cisplatin, carboplatin and their combination chemotherapy drugs (review).

Boulikas, Teni / Vougiouka, Maria

Oncology reports

2004 Volume 11, Issue 3, Page(s) 559–595

Abstract: Cisplatin continues to play a central role in cancer chemotherapy in spite of its toxicity. It is used as first-line chemotherapy against epithelial malignancies of lung, ovarian, bladder, testicular, head and neck, esophageal, gastric, colon and ... ...

Abstract	Cisplatin continues to play a central role in cancer chemotherapy in spite of its toxicity. It is used as first-line chemotherapy against epithelial malignancies of lung, ovarian, bladder, testicular, head and neck, esophageal, gastric, colon and pancreatic but also as second- and third-line treatment against a number of metastatic malignancies including cancers of the breast, melanoma, prostate, mesothelioma, leiomyosarcomas, malignant gliomas and others. Cisplatin has become the gold standard treatment against cervical cancer in combination with radiotherapy. This review summarizes the state of the art on clinical trials published mainly in 2002 using cisplatin and carboplatin in their combinations with other anticancer drugs. For most advanced cancers the response rate to chemotherapy is about 50% in first-line treatments and about 15% in second- or third-line treatments; for example response rates of 25-50% have been observed for chemonaive patients with advanced non-small cell lung cancer treated with cisplatin or carboplatin in combination with gemcitabine or taxanes and in exceptional cases these rates are up to 80% with addition of radiotherapy. Response rates are very discouraging in second- or third-line chemotherapy treatments (7-25%). Despite an increase in response rate from the use of modern-day chemotherapy drugs, no major difference in long-term survival has been achieved. It is a high priority to invent novel approaches for cancer treatment. It is hoped that a fraction of the numerous experimental drugs will show virtues in the anticancer arena especially combined with existing treatment regimens. Efforts should focus on diminution of side effects improving the quality of life of the patient. A preferential tumor targeting of chemotherapy treatments would bring a revolution in molecular medicine and would greatly advance cancer therapy in the upcoming years.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Carboplatin/administration & dosage ; Carboplatin/therapeutic use ; Cisplatin/administration & dosage ; Cisplatin/therapeutic use ; Clinical Trials as Topic ; Female ; Humans ; Male ; Neoplasms/drug therapy ; Neoplasms/mortality ; Treatment Outcome
Chemical Substances	Carboplatin (BG3F62OND5) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2004-03
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	1222484-4
ISSN	1791-2431 ; 1021-335X
ISSN (online)	1791-2431
ISSN	1021-335X
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 4213: Show issues

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Article: Viral and non-viral vectors in gene therapy: technology development and clinical trials.

Lundstrom, Kenneth / Boulikas, Teni

Technology in cancer research & treatment

2003 Volume 2, Issue 5, Page(s) 471–486

Abstract: Gene therapy as part of modern molecular medicine holds great promise for the treatment of both acute and chronic diseases and has the potential to bring a revolutionary era to cancer treatment. Gene therapy has been named the medicine of the future. For ...

Abstract	Gene therapy as part of modern molecular medicine holds great promise for the treatment of both acute and chronic diseases and has the potential to bring a revolutionary era to cancer treatment. Gene therapy has been named the medicine of the future. For the past 10 years various viral and non-viral vectors have been engineered for improved gene and drug delivery. Although various diseases have been targeted, cancer therapy has been addressed to a large extent because of the straight forward approach. Delivery of toxic or immunostimulatory genes by viral and non-viral vectors has been investigated and encouraging results have been obtained in animal models. A large number of clinical trials have been conducted with some highly promising outcome. We propose that combinations of viruses with liposomes or polymers will solve the problem of systemic viral delivery and tumor targeting, bringing a revolution in molecular medicine and in applications of gene therapy in humans.
MeSH term(s)	Animals ; Biotechnology/instrumentation ; Biotechnology/methods ; Clinical Trials as Topic ; Genetic Therapy/instrumentation ; Genetic Therapy/methods ; Genetic Vectors/genetics ; Humans ; Immunotherapy/methods ; Neoplasms/genetics ; Neoplasms/pathology ; Neoplasms/therapy
Language	English
Publishing date	2003-10
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2146365-7
ISSN	1533-0338 ; 1533-0346
ISSN (online)	1533-0338
ISSN	1533-0346
DOI	10.1177/153303460300200513
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Zs.A 5871: Show issues

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Article: Cisplatin and platinum drugs at the molecular level. (Review).

Boulikas, Teni / Vougiouka, Maria

Oncology reports

2003 Volume 10, Issue 6, Page(s) 1663–1682

Abstract: Over twenty years of intensive work toward improvement of cisplatin, and with hundreds of platinum drugs tested, has resulted in the introduction of the widely used carboplatin and of oxaliplatin used only for a very narrow spectrum of cancers. A number ... ...

Abstract	Over twenty years of intensive work toward improvement of cisplatin, and with hundreds of platinum drugs tested, has resulted in the introduction of the widely used carboplatin and of oxaliplatin used only for a very narrow spectrum of cancers. A number of interesting platinum compounds including the orally administered platinum drug JM216, nedaplatin, the sterically hindered platinum(II) complex ZD0473, the trinuclear platinum complex BBR3464, and the liposomal forms Lipoplatin and SPI-77 are under clinical evaluation. This review summarizes the molecular mechanisms of platinum compounds for DNA damage, DNA repair and induction of apoptosis via activation or modulation of signaling pathways and explores the basis of platinum resistance. Cisplatin, carboplatin, oxaliplatin and most other platinum compounds induce damage to tumors via induction of apoptosis; this is mediated by activation of signal transduction leading to the death receptor mechanisms as well as mitochondrial pathways. Apoptosis is responsible for the characteristic nephrotoxicity, ototoxicity and most other toxicities of the drugs. The major limitation in the clinical applications of cisplatin has been the development of cisplatin resistance by tumors. Mechanisms explaining cisplatin resistance include the reduction in cisplatin accumulation inside cancer cells because of barriers across the cell membrane, the faster repair of cisplatin adducts, the modulation of apoptotic pathways in various cells, the upregulation in transcription factors, the loss of p53 and other protein functions and a higher concentration of glutathione and metallothioneins in some type of tumors. A number of experimental strategies to overcome cisplatin resistance are at the preclinical or clinical level such as introduction of the bax gene, inhibition of the JNK pathway, introduction of a functional p53 gene, treatment of tumors with aldose reductase inhibitors and others. Particularly important are combinations of platinum drug treatments with other drugs, radiation and the emerging gene therapy regimens.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Apoptosis ; Cisplatin/pharmacology ; DNA/drug effects ; DNA/metabolism ; Disease Progression ; Gene Expression Regulation, Neoplastic ; Genes, p53 ; Genetic Therapy ; Humans ; Liposomes/metabolism ; Models, Chemical ; Models, Molecular ; Mutation ; Neoplasms/drug therapy ; Nucleic Acid Conformation ; Platinum/pharmacology ; Prognosis ; Signal Transduction
Chemical Substances	Antineoplastic Agents ; Liposomes ; lipoplatin ; Platinum (49DFR088MY) ; DNA (9007-49-2) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2003-11
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	1222484-4
ISSN	1791-2431 ; 1021-335X
ISSN (online)	1791-2431
ISSN	1021-335X
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Zs.A 4213: Show issues

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Article: Potential of the Akt inhibitor LY294005 to antagonize the efficacy of Cisplatin against HCT116 tumor cells in a DNA mismatch repair-dependent manner.

Fedier, Andre / Erdmann, Ruediger / Boulikas, Teni / Fink, Daniel

International journal of oncology

2006 Volume 29, Issue 5, Page(s) 1303–1310

Abstract: Human colorectal adenocarcinoma sublines either deficient (HCT116+ch2) or proficient (HCT116+ch3) in the function of MLH1, one of five proteins crucial to DNA mismatch repair (MMR), were used to investigate whether the Akt-specific inhibitor LY294005 ... ...

Abstract	Human colorectal adenocarcinoma sublines either deficient (HCT116+ch2) or proficient (HCT116+ch3) in the function of MLH1, one of five proteins crucial to DNA mismatch repair (MMR), were used to investigate whether the Akt-specific inhibitor LY294005 could not only increase the efficacy of platinum drugs in HCT116 cells in general but also increase the efficacy of the cisplatinum compounds Cisplatin and Lipoplatin specifically in MLH1-deficient, Cisplatin- and Lipoplatin-resistant HCT116 cells. We report that, under the conditions it increased the efficacy of Docetaxel and did not affect that of 6-thioguanine, LY294005 decreased the sensitivity of both sublines to Cisplatin, Lipoplatin, Oxaliplatin, and Lipoxal. Notably, the LY294005-imposed decrease was significantly higher in the MLH1-proficient than in the MLH1-deficient subline with Cisplatin and Lipoplatin, whereas it was nearly the same in both sublines with Oxaliplatin and Lipoxal. These LY294005-imposed changes in drug sensitivity, i.e. increase with Docetaxel and decreases with platinum compounds, were not associated with the concomitant abrogation in the levels of phospho-Aktser473. Analogous changes in drug sensitivity were also observed with the PI3-kinase inhibitor LY294002, but these changes were associated with complete abrogation of phospho-Aktser473. These observations suggest a possible relationship between MMR-mediated cisplatinum DNA damage signaling and the Akt signaling pathway, e.g. a common target for both pathways. A possibly novel property of Akt in aggravating drug sensitivity may also be proposed.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Adenocarcinoma/drug therapy ; Adenocarcinoma/genetics ; Antineoplastic Agents/antagonists & inhibitors ; Antineoplastic Agents/therapeutic use ; Base Pair Mismatch/drug effects ; Carrier Proteins/genetics ; Chromones/pharmacology ; Cisplatin/antagonists & inhibitors ; Cisplatin/therapeutic use ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; DNA Repair/drug effects ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Humans ; Inositol/analogs & derivatives ; Inositol/pharmacology ; Morpholines/pharmacology ; MutL Protein Homolog 1 ; Nuclear Proteins/genetics ; Organoplatinum Compounds/antagonists & inhibitors ; Organoplatinum Compounds/therapeutic use ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Taxoids/therapeutic use ; Tumor Cells, Cultured
Chemical Substances	1L-6-hydroxymethyl-chiro-inositol 2(R)-2-O-methyl-3-O-octadecylcarbonate ; Adaptor Proteins, Signal Transducing ; Antineoplastic Agents ; Carrier Proteins ; Chromones ; MLH1 protein, human ; Morpholines ; Nuclear Proteins ; Organoplatinum Compounds ; Protein Kinase Inhibitors ; Taxoids ; oxaliplatin (04ZR38536J) ; docetaxel (15H5577CQD) ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; Inositol (4L6452S749) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2006-11
Publishing country	Greece
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1154403-x
ISSN	1019-6439
ISSN	1019-6439
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Zs.A 3690: Show issues

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Article: Liposomal oxaliplatin in the treatment of advanced cancer: a phase I study.

Stathopoulos, George P / Boulikas, Teni / Kourvetaris, Andreas / Stathopoulos, John

Anticancer research

2006 Volume 26, Issue 2B, Page(s) 1489–1493

Abstract: Background: Lipoxal is a liposomal oxaliplatin, which reduces the cytotoxic agent's adverse reactions without reducing effectiveness. Our objectives were to determine the adverse reactions, dose-limiting toxicity (DLT) and the maximum tolerated dose ( ... ...

Abstract	Background: Lipoxal is a liposomal oxaliplatin, which reduces the cytotoxic agent's adverse reactions without reducing effectiveness. Our objectives were to determine the adverse reactions, dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD) of lipoxal. Patients and methods: Twenty-seven patients with advanced disease of the gastrointestinal system were included in the study. All patients had been pretreated with standard chemotherapy according to established guidelines. At entry, all patients had recurrent or progressive disease (stage IV gastrointestinal cancers: colorectal, gastric and pancreatic). Six lipoxal dose levels (100 mg/m2, 150 mg/m2, 200 mg/m2, 250 mg/m2, 300 mg/m2 and 350 mg/m2) were set and at least 3 patients were included at each level. Eight patients were treated at 300 mg/m2 (MTD). The treatment was given once weekly for 8 weeks. Results: No serious side-effects were observed at the first 4 dose levels (100-250 mg/m2). At levels 5 and 6, mild myelotoxicity and nausea were observed. The most common adverse reaction was grade 2-3 peripheral neuropathy, observed in all 4 patients treated at 350 mg/m2. The 350 mg/m2 dose level was therefore considered as DLT and the 300 mg/m2 level as the MTD. Of the 27 patients, 3 achieved partial response and 18 had stable disease for 4 months, (range 2-9 months). Conclusion: The most common toxicity was peripheral neuropathy at the 300 and 350 mg/m2 dose levels. Lipoxal was well-tolerated and greatly reduced all the other side-effects of oxaliplatin, especially myelotoxicity and gastrointestinal tract toxicities. These preliminary results showed adequate effectiveness in pretreated patients.
MeSH term(s)	Adult ; Aged ; Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacokinetics ; Dose-Response Relationship, Drug ; Female ; Humans ; Liposomes ; Male ; Middle Aged ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Organoplatinum Compounds/administration & dosage ; Organoplatinum Compounds/adverse effects ; Organoplatinum Compounds/pharmacokinetics ; Patient Compliance
Chemical Substances	Antineoplastic Agents ; Liposomes ; Organoplatinum Compounds ; oxaliplatin (04ZR38536J)
Language	English
Publishing date	2006-03
Publishing country	Greece
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1642: Show issues

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Article: MLH1-deficient tumor cells are resistant to lipoplatin, but retain sensitivity to lipoxal.

Fedier, André / Poyet, Cédric / Perucchini, Daniele / Boulikas, Teni / Fink, Daniel

Anti-cancer drugs

2006 Volume 17, Issue 3, Page(s) 315–323

Abstract: Lipoplatin, currently under phase III evaluation, is a novel liposomal cisplatin formulation highly effective against cancers. Lipoplatin has eliminated or reduced the systemic toxicity frequently seen for cisplatin. The objective of the present study ... ...

Abstract	Lipoplatin, currently under phase III evaluation, is a novel liposomal cisplatin formulation highly effective against cancers. Lipoplatin has eliminated or reduced the systemic toxicity frequently seen for cisplatin. The objective of the present study was to determine whether the cytotoxic effect of lipoplatin is dependent on the functional integrity of DNA mismatch repair (MMR), a post-replicative DNA repair machinery implicated in cell cycle control and apoptosis. Clonogenic data revealed a significant (P<0.05) 2-fold resistance to lipoplatin of HCT116 human colorectal adenocarcinoma cells lacking MLH1, one of five proteins crucial to MMR function, as compared to MLH1-expressing HCT116 cells. In addition, MLH1-deficient cells were at least 3-fold less susceptible to apoptosis (DNA fragmentation) than MLH1-proficient cells. However, proteolytic processing of caspase-3, caspase-7 and poly(ADP-ribose)polymerase-1 following lipoplatin treatment was comparable in MLH1-deficient cells and -proficient cells. Furthermore, MLH1-deficient cells retained the ability to attenuate cell cycle progression past the G2/M checkpoint following lipoplatin treatment. In conclusion, our results indicate that the lipoplatin-sensitive phenotype of MLH1-proficient cells correlated with increased apoptosis which may occur via caspase-independent pathways. They also suggest that the integrity of MMR function is a relevant determinant accounting for the cytotoxicity of lipoplatin. However, this does not seem to apply to lipoxal, a novel liposomal formulation of oxaliplatin, because MLH1-deficient cells were as sensitive to lipoxal as MLH1-proficient cells.
MeSH term(s)	Adaptor Proteins, Signal Transducing ; Adenocarcinoma/drug therapy ; Adenocarcinoma/pathology ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Apoptosis/physiology ; Carrier Proteins/physiology ; Cell Division/drug effects ; Cell Line, Tumor ; Cisplatin/pharmacology ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/pathology ; DNA Repair ; Drug Resistance, Neoplasm ; G2 Phase/drug effects ; HCT116 Cells ; Humans ; Liposomes/administration & dosage ; MutL Protein Homolog 1 ; Necrosis ; Nuclear Proteins/deficiency ; Nuclear Proteins/physiology ; Organoplatinum Compounds/administration & dosage ; Oxaliplatin
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antineoplastic Agents ; Carrier Proteins ; Liposomes ; MLH1 protein, human ; Nuclear Proteins ; Organoplatinum Compounds ; lipoplatin ; Oxaliplatin (04ZR38536J) ; MutL Protein Homolog 1 (EC 3.6.1.3) ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2006-01-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1065301-6
ISSN	1473-5741 ; 0959-4973
ISSN (online)	1473-5741
ISSN	0959-4973
DOI	10.1097/00001813-200603000-00010
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Zs.A 3125: Show issues

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Article: Safety and efficacy of quadrapeutics versus chemoradiation in head and neck carcinoma xenograft model.

Lukianova-Hleb, Ekaterina Y / Kim, Yoo-Shin / Aryasomayajula, Bhawani / Boulikas, Teni / Phan, Jack / Hung, Mien-Chie / Torchilin, Vladimir P / O'Neill, Brian E / Lapotko, Dmitri O

American journal of cancer research

2015 Volume 5, Issue 12, Page(s) 3534–3547

Abstract: Chemoradiation is the strongest anti-tumor therapy but in resistant unresectable cancers it often lacks safety and efficacy. We compared our recently developed cell-level combination approach, quadrapeutics, to chemoradiation therapy to establish pre- ... ...

Abstract	Chemoradiation is the strongest anti-tumor therapy but in resistant unresectable cancers it often lacks safety and efficacy. We compared our recently developed cell-level combination approach, quadrapeutics, to chemoradiation therapy to establish pre-clinical data for its biodistribution, safety and efficacy in head and neck squamous cell carcinoma (HNSCC), as a clinically challenging aggressive and resistant cancer. In vitro and in vivo models of four carcinomas were treated with standard chemoradiation and quadrapeutics using identical drug and radiation doses. We applied liposomal cisplatin or doxorubicin, colloidal gold, near-infrared laser pulses and radiation, all at low safe doses. The final evaluation used a xenograft model of HNSCC. Quadrapeutics enhanced standard chemoradiation in vitro by reducing head and neck cancer cell proliferation by 1000-fold, inhibiting tumor growth in vivo by 34-fold and improving animal survival by 5-fold, and reducing the side effects to a negligible level. In quadrapeutics, we observed an "inversion" of the drug efficacy of two standard drugs: doxorubicin, a low efficacy drug for the cancers studied, was two times more efficient than cisplatin, the first choice drug in clinic for HNSCC. The radical therapeutic gain of quadrapeutics resulted from the intracellular synergy of the four components employed which we administered in a specific sequence, while the reduction in the toxicity was due to the low doses of all four components. The biodistribution, safety and efficacy data for quadrapeutics in HNSCC ensure its high translational potential and justify the possibility of clinical trials.
Language	English
Publishing date	2015-11-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2589522-9
ISSN	2156-6976
ISSN	2156-6976
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Systemic Lipoplatin infusion results in preferential tumor uptake in human studies.

Boulikas, Teni / Stathopoulos, Georgios P / Volakakis, Nikolaos / Vougiouka, Maria

Anticancer research

2005 Volume 25, Issue 4, Page(s) 3031–3039

Abstract: Lipoplatin, a liposomal formulation of cisplatin, was developed with almost negligible nephrotoxicity, ototoxicity and neurotoxicity, as demonstrated in preclinical and Phase I human studies. A polyethylene-glycol coating of the liposome nanoparticles is ...

Abstract	Lipoplatin, a liposomal formulation of cisplatin, was developed with almost negligible nephrotoxicity, ototoxicity and neurotoxicity, as demonstrated in preclinical and Phase I human studies. A polyethylene-glycol coating of the liposome nanoparticles is supposed to result in tumor accumulation of the drug by extravasation through the altered tumor vasculature. We explored the hypothesis that intravenous infusion of Lipoplatin results in tumor targeting in four independent patient cases (one with hepatocellular adenocarcinoma, two with gastric cancer and one with colon cancer) who underwent Lipoplatin infusion followed by a prescheduled surgery approximately 20 h later. Direct measurement of the platinum levels in specimens from the excised tumors and normal tissues showed that the total platinum levels were on average 10-50 times higher in malignant tissue compared to the adjacent normal tissue specimens; most effective targeting was observed in colon cancer, with an accumulation up to 200-fold higher in colon tumors compared to normal colon tissue. Of the several surgical specimens, gastric tumors displayed the highest levels of total platinum suggesting Lipoplatin as a candidate anticancer agent for gastric tumors; gastric tumor specimens had up to 260 micrograms platinum /g tissue, that was higher than any tissue level in animals treated at much higher doses. Fat tissue displayed a high accumulation of total platinum in surgical specimens in three different patients, correlating to the lipid capsule of cisplatin in its Lipoplatin formulation. It was also inferred that normal tissue had more platinum trapped in the tissue but not reacted with macromolecules, whereas tumor tissue displayed platinum that reacted with cellular macromolecules; the data were consistent with a model where Lipoplatin damages more tumor compared to normal cells. In conclusion, Lipoplatin has the ability to preferentially concentrate in malignant tissue both of primary and metastatic origin following intravenous infusion to patients. In this respect, Lipoplatin emerges as a very promising drug in the arsenal of chemotherapeutics.
MeSH term(s)	Adipose Tissue/metabolism ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacokinetics ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/metabolism ; Cisplatin/administration & dosage ; Cisplatin/pharmacokinetics ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/metabolism ; Digestive System Neoplasms/drug therapy ; Digestive System Neoplasms/metabolism ; Digestive System Neoplasms/pathology ; Female ; Humans ; Infusions, Intravenous ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/secondary ; Male ; Middle Aged ; Stomach Neoplasms/drug therapy ; Stomach Neoplasms/metabolism ; Stomach Neoplasms/pathology
Chemical Substances	Antineoplastic Agents ; lipoplatin ; Cisplatin (Q20Q21Q62J)
Language	English
Publishing date	2005-07
Publishing country	Greece
Document type	Clinical Trial ; Journal Article
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
Database	MEDical Literature Analysis and Retrieval System OnLINE

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