-
International Journal of Radiation... Jan 2010Aplidin (plitidespin) is a novel cyclic depsipeptide, currently in Phase II clinical trials for solid and hematologic malignancies. We examined the effects of oxygen on...
PURPOSE
Aplidin (plitidespin) is a novel cyclic depsipeptide, currently in Phase II clinical trials for solid and hematologic malignancies. We examined the effects of oxygen on the cytotoxicity of Aplidin and the interactions between Aplidin and radiation. These factors will be important if Aplidin is used clinically in combination with radiotherapy.
MATERIALS
Exponentially-growing EMT6 mouse mammary tumour cells in monolayer cultures were treated with Aplidin and 250 kV X-rays.
RESULTS
The cytotoxicity of Aplidin was not altered either by incubation in moderate hypoxia before and during a 24 h drug treatment or by incubation in severe hypoxia before and during a 2 h drug treatment. Treatment with Aplidin plus radiation produced cytotoxicities compatible with additive or supraadditive cytotoxicities. Cells treated with 1 microM Aplidin for 24 h then killed by 100 Gy of radiation were toxic to untreated cells co-cultured with them.
CONCLUSIONS
The cytotoxicity of Aplidin is independent of the oxygenation during treatment. Aplidin, or an active metabolite of Aplidin, is retained in the cells and later released as the radiation-sterilised cells die, producing a Bystander effect that kills neighbouring cells. This Bystander effect could affect the outcome of therapeutic regimens combining Aplidin and radiation.
Topics: Animals; Bystander Effect; Cell Hypoxia; Cell Line, Tumor; Depsipeptides; Mice; Neoplasms; Peptides, Cyclic; Radiation Tolerance
PubMed: 20070217
DOI: 10.3109/09553000903264531 -
Methods and Findings in Experimental... Oct 2009[Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine...
[Methoxy-11c]PD-153035; Afamelanotide, Agalsidase beta, Alemtuzumab, Alkaline phosphatase, Amlodipine, Anecortave acetate, Apixaban, Aripiprazole, Atomoxetine hydrochloride; Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brimonidine tartrate/timolol maleate, Brivudine; Canakinumab, Cetuximab, Chlorotoxin, Cinaciguat; Dapagliflozin, Decitabine, Duloxetine hydrochloride; Elagolix sodium, Eplerenone, Eritoran tetrasodium, Escitalopram oxalate, Etoricoxib, Ezetimibe; Fospropofol disodium; G-207, Gabapentin enacarbil, Gefitinib, Golimumab; Human plasmin; Inotuzumab ozogamicin, Insulin glargine, Insulin glulisine, Istaroxime, Ixabepilone; KLH; Levodopa/carbidopa/entacapone; Miglustat, Mitumprotimut-T, MP-470; Oblimersen sodium, Olmesartan medoxomil; P53-SLP, PAN-811, Patupilone, Pazopanib hydrochloride, PC-515, Peginterferon alfa-2a, Pegylated arginine deiminase 20000, Pemetrexed disodium, Plitidepsin, Pregabalin; Rasagiline mesilate, Rotigotine; SCH-697243, Sirolimus-eluting stent, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tadalafil, Tapentadol hydrochloride, TMC-207; V-211, Valganciclovir hydrochloride; Zolpidem tartrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 19967103
DOI: No ID Found -
Journal of Chemotherapy (Florence,... Nov 2009Plitidepsin (Aplidin) is a novel antitumor agent, derived from the mediterranean tunicate Aplidium albicans, and is currently in phase ii clinical trials with evidence...
Plitidepsin (Aplidin) is a novel antitumor agent, derived from the mediterranean tunicate Aplidium albicans, and is currently in phase ii clinical trials with evidence of activity in heavily pretreated multiple myeloma, renal cell carcinoma, melanoma and neuroblastoma patients. As compared to its parental compound didemnin B, plitidepsin has shown a better therapeutic index with less bone marrow toxicity, cardiotoxicity and neurotoxicity in patients and a more potent cytotoxic effect in several tumor cell lines. As sensitivity to the drug varies between cell lines and fresh leukemia samples, we performed studies on transport of plitidepsin in leukemia and lymphoma cell lines to determine the mechanism of uptake. The drug is taken up by an active transport process, i.e. the process is temperature and energy dependent, and has a high-affinity binding site with Kt =212 nM and Vmax = 15 pmoles/min. Importantly, once inside the cell, efflux of plitidepsin is minimum, suggesting that the drug is bound to intracellular macromolecules. Further work showed that plitidepsin binds to G-Protein Coupled Receptors (GPCRs), since GPCR and GRK (GPCR kinases) inhibitors suramin and heparin respectively, markedly reduce the drug uptake and its cytotoxic activity. Signaling via Jak/Stat pathway is inhibited by pharmacological concentrations of plitidepsin, further confirming the relationship between plitidepsin and GPCRs.
Topics: 4-Aminopyridine; Adenosine Triphosphate; Antimetabolites, Antineoplastic; Biological Transport, Active; Cell Proliferation; Cytarabine; Depsipeptides; Heparin; Humans; JNK Mitogen-Activated Protein Kinases; Membrane Microdomains; Peptides, Cyclic; Potassium Channel Blockers; Potassium Channels; Receptors, G-Protein-Coupled; STAT Transcription Factors; Subcellular Fractions; Suramin; Time Factors; Tumor Cells, Cultured
PubMed: 19933047
DOI: 10.1179/joc.2009.21.5.550 -
Methods and Findings in Experimental... Sep 2009Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Integrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: AAV1/SERCA2a, Abacavir sulfate/lamivudine, Adalimumab, Aliskiren fumarate, Ambrisentan, Aripiprazole, AT-7519, Atazanavir sulfate, Atomoxetine hydrochloride, Azacitidine, Azelnidipine; Besifloxacin hydrochloride, Bevacizumab, Bioabsorbable everolimus-eluting coronary stent, Bortezomib, Bosentan, Budesonide/formoterol fumarate; CAIV-T, Carisbamate, Casopitant mesylate, Certolizumab pegol, Cetuximab, Ciclesonide, Ciprofloxacin/dexamethasone, CTCE-9908; Dalcetrapib, Darunavir, Deferasirox, Desloratadine, Disitertide, Drotrecogin alfa (activated), DTA-H19, Duloxetine hydrochloride, Dutasteride; Ecogramostim, Efalizumab, Emtricitabine, Eribulin mesilate, Escitalopram oxalate, Eszopiclone, EUR-1008, Everolimus-eluting coronary stent, Exenatide; Fampridine, Fluticasone furoate, Formoterol fumarate/fluticasone propionate, Fosamprenavir calcium, Fulvestrant; Gabapentin enacarbil, GS-7904L; HPV-6/11/16/18, Human Secretin, Hydralazine hydrochloride/isosorbide dinitrate; Imatinib mesylate, Imexon, Inalimarev/Falimarev, Indacaterol, Indacaterol maleate, Inhalable human insulin, Insulin detemir, Insulin glargine, Ixabepilone; L-Alanosine, Lapatinib ditosylate, Lenalidomide, Levocetirizine dihydrochloride, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Loratadine/montelukast sodium, Lutropin alfa; MeNZB, Mepolizumab, Micafungin sodium, Morphine hydrochloride; Nabiximols, Nikkomycin Z; Olmesartan medoxomil, Omalizumab; Paclitaxel-eluting stent, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Perifosine, PF-489791, Plitidepsin, Posaconazole, Pregabalin; QAX-576; Raltegravir potassium, Ramelteon, Rasagiline mesilate, Recombinant human relaxin H2, rhGAD65, Rivaroxaban, Rosuvastatin calcium, Rotigotine; Saxagliptin, SCH-530348, Sirolimus-eluting stent, SLIT-amikacin, Sorafenib, Sotrastaurin, SR-16234, Sulforaphane; Tadalafil, Tanespimycin, Tapentadol hydrochloride, Teriparatide, Tesofensine, Tiotropium bromide, Tipifarnib, Tirapazamine, TMC-207, Tocilizumab, Tolvaptan, Tosedostat, Treprostinil sodium; Ustekinumab; Varespladib methyl, Vicriviroc, Vildagliptin, Vildagliptin/metformin hydrochloride, Volociximab, Voriconazole; Ziconotide, Ziprasidone hydrochloride.
Topics: Clinical Trials as Topic; Humans
PubMed: 19907722
DOI: No ID Found -
Marine Drugs Sep 2009The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m(2)) administered as a 3-hour continuous... (Clinical Trial)
Clinical Trial
The objective of this exploratory, open-label, single-arm, phase II clinical trial was to evaluate plitidepsin (5 mg/m(2)) administered as a 3-hour continuous intravenous infusion every two weeks to patients with locally advanced/metastatic transitional cell carcinoma of the urothelium who relapsed/progressed after first-line chemotherapy. Treatment cycles were repeated for up to 12 cycles or until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. The primary efficacy endpoint was objective response rate according to RECIST. Secondary endpoints were the rate of SD lasting > or = 6 months and time-to-event variables. Toxicity was assessed using NCI-CTC v. 3.0. Twenty-one patients received 57 treatment cycles. No objective tumor responses occurred. SD lasting <6 months was observed in two of 18 evaluable patients. With a median follow-up of 4.6 months, the median PFR and the median OS were 1.4 months and 2.3 months, respectively. The most common AEs were mild to moderate nausea, fatigue, myalgia and anorexia. Anemia, lymphopenia, and increases in transaminases, alkaline phosphatase and creatinine were the most frequent laboratory abnormalities. No severe neutropenia occurred. Treatment was feasible and generally well tolerated in this patient population; however the lack of antitumor activity precludes further studies of plitidepsin in this setting.
Topics: Adult; Aged; Carcinoma, Transitional Cell; Depsipeptides; Disease Progression; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Metastasis; Peptides, Cyclic; Urinary Bladder Neoplasms; Urothelium
PubMed: 19841725
DOI: 10.3390/md7030451 -
American Journal of Clinical Oncology Feb 2010To evaluate the antitumor response, time-to-event efficacy endpoints and toxicity of plitidepsin (Aplidin) 5 mg/m as a 3-hour intravenous (i.v.) infusion every 2 weeks...
OBJECTIVES
To evaluate the antitumor response, time-to-event efficacy endpoints and toxicity of plitidepsin (Aplidin) 5 mg/m as a 3-hour intravenous (i.v.) infusion every 2 weeks in patients with unresectable advanced medullary thyroid carcinoma (MTC).
METHODS
Sixteen patients with MTC and disease progression or large tumor burden received plitidepsin. Tumor response and time-related parameters were evaluated according to Response Evaluation Criteria in Solid Tumors. Secondary efficacy endpoints were marker response (calcitonin and carcinoembryonic antigen), clinical benefit and quality of life. Safety was assessed using the National Cancer Institute Common Toxicity Criteria.
RESULTS
A total of 141 cycles (median, 9 per patient; range, 1-24) were administered. No complete responses or partial responses (PR) were found, and 12 patients had stable disease for >8 weeks. Median follow-up was 15.0 months. Median time to progression was 5.3 months. Median overall survival could not be calculated, but 86.7% and 66.0% of patients were alive at 6 and 12 months. Marker response included 1 unconfirmed PR and 2 stabilizations for calcitonin, and 1 unconfirmed PR and 4 stabilizations for calcitonin and carcinoembryonic antigen. One patient showed clinical benefit. Quality of life scores generally decreased during the study. Most treatment-related adverse events were mild or moderate. Grade 3 lymphopenia was the only severe hematological toxicity found (2 patients). Severe nonhematological toxicities were grade 3 creatine phosphokinase increase (2 patients, with no myalgia or muscular weakness) and transient grade 3 alanine aminotransferase increase (5 patients).
CONCLUSIONS
Single-agent plitidepsin given as 3-hour i.v. infusions every 2 weeks was generally well tolerated but showed limited clinical activity in patients with unresectable advanced MTC.
Topics: Adult; Aged; Brain Stem Neoplasms; Depsipeptides; Female; Humans; Infusions, Intravenous; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Staging; Peptides, Cyclic; Prognosis; Survival Rate; Thyroid Neoplasms; Treatment Outcome
PubMed: 19704366
DOI: 10.1097/COC.0b013e31819fdf5e -
American Journal of Clinical Oncology Apr 2010To assess clinical benefit of plitidepsin (Aplidine) in patients with advanced medullary thyroid carcinoma (MTC).
OBJECTIVES
To assess clinical benefit of plitidepsin (Aplidine) in patients with advanced medullary thyroid carcinoma (MTC).
MATERIALS AND METHODS
We retrospectively reported the outcome of 10 patients with advanced MTC among 215 patients who have entered the phase I program with plitidepsin.
RESULTS
Median number of cycles was 5. Using World Health Organization criteria, 1 among 5 patients with measurable disease displayed a confirmed partial response, whereas 8 patients experienced a stable disease, and 1 patient had a progressive disease, corresponding to a disease control rate of 90%. Two patients treated at the maximum tolerated dose experienced muscular dose-limiting toxicity possibly related to palmitoyl transferase inhibition. One of these 2 patients was able to continue therapy with no dose reduction with the prophylactic addition of l-carnitine, which is used in the treatment of the carnitine palmitoyl transferase deficiency type 2.
DISCUSSION
Plitidepsin seems to be able to induce clinical benefit in patients with pretreated MTC, and its toxicity has been manageable at the recommended dose.
Topics: Adult; Aged; Antineoplastic Agents; Bone Neoplasms; Carcinoma, Medullary; Depsipeptides; Female; Follow-Up Studies; Humans; Liver Neoplasms; Lung Neoplasms; Male; Marine Toxins; Maximum Tolerated Dose; Middle Aged; Peptides, Cyclic; Survival Rate; Thyroid Neoplasms; Treatment Outcome
PubMed: 19687728
DOI: 10.1097/COC.0b013e318199fb6e -
Methods and Findings in Experimental... May 2009(-)-Gossypol; Abacavir sulfate/lamivudine, ACAM-1000, ACE-011, Agomelatine, AGS-004, Alemtuzumab, Alvocidib hydrochloride, AMG-317, Amlodipine, Aripiprazole, Atazanavir...
(-)-Gossypol; Abacavir sulfate/lamivudine, ACAM-1000, ACE-011, Agomelatine, AGS-004, Alemtuzumab, Alvocidib hydrochloride, AMG-317, Amlodipine, Aripiprazole, Atazanavir sulfate, Azacitidine; Becatecarin, Belinostat, Bevacizumab, BMS-387032, BMS-690514, Bortezomib; Casopitant mesylate, Cetuximab, Choline fenofibrate, CK-1827452, Clofarabine, Conivaptan hydrochloride; Dabigatran etexilate, DADMe-Immucillin-H, Darbepoetin alfa, Darunavir, Dasatinib, DC-WT1, Decitabine, Deferasirox, Degarelix acetate, Denenicokin, Denosumab, Dienogest, Duloxetine hydrochloride; Ecogramostim, Eculizumab, Edoxaban tosilate, Elacytarabine, Elesclomol, Eltrombopag olamine, Enfuvirtide, Enzastaurin hydrochloride, Eribulin mesilate, Erlotinib hydrochloride, Escitalopram oxalate, Eszopiclone, Etravirine; Flibanserin, Fludarabine, Fondaparinux sodium, Fosamprenavir calcium; Gefitinib, Genistein; I-131-L19-SIP, Idrabiotaparinux sodium, Imatinib mesylate, IMGN-901, Ipilimumab; Laromustine, Lenalidomide, Liposomal cisplatin, Liraglutide, Lisdexamfetamine mesilate, Lopinavir, Lopinavir/ritonavir; Maraviroc, MDV-3100, Mecasermin rinfabate, MP-470, Mycophenolic acid sodium salt; Naproxcinod, NB-002, Nesiritide, Nilotinib hydrochloride monohydrate, NK-012; Palonosetron hydrochloride, Panobinostat, Pegfilgrastim, Peginterferon alfa-2a, Pitavastatin calcium, PL-3994, Plerixafor hydrochloride, Plitidepsin, PM-10450; Raltegravir potassium, Recombinant human soluble thrombomodulin, ReoT3D, RHAMM R3 peptide, Rivaroxaban, Romiplostim, Rosuvastatin calcium, Rozrolimupab; Sabarubicin hydrochloride, Salinosporamide A, Sirolimus-eluting stent, Smallpox (Vaccinia) Vaccine, Live, Sorafenib; Tenofovir disoproxil fumarate, Tenofovir disoproxil fumarate/emtricitabine, Teriparatide, Tipifarnib, Tipranavir, Trabectedin, Trifluridine/TPI; Vardenafil hydrochloride hydrate, Vinflunine, Volociximab, Vorinostat; Ximelagatran; Yttrium 90 (90Y) ibritumomab tiuxetan; Ziprasidone hydrochloride, Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 19557204
DOI: 10.1358/mf.2009.31.4.1373959 -
Current Opinion in Investigational... Jun 2009Plitidepsin (PharmaMar SA) is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans, and has demonstrated strong anticancer activity... (Review)
Review
Plitidepsin (PharmaMar SA) is a cyclodepsipeptide originally isolated from the Mediterranean tunicate Aplidium albicans, and has demonstrated strong anticancer activity against a large variety of cultured human cancer cells and in xenografted mice. Phase I/II clinical trials of plitidepsin yielded promising results of anticancer activity in patients with cancer. Several studies have revealed that plitidepsin induces cell cycle arrest or apoptosis in a cell type- and dose-dependent manner. These effects are related to the induction of early oxidative stress, the activation of Rac1 GTPase and the inhibition of protein phosphatases, which in conjunction cause the sustained activation of JNK and p38 MAPK. This review outlines the current knowledge of plitidepsin activity, with a primary focus on the molecular mechanisms of action of the compound.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Clinical Trials as Topic; Depsipeptides; Humans; Models, Biological; Neovascularization, Physiologic; Peptides, Cyclic; Signal Transduction
PubMed: 19513942
DOI: No ID Found -
Melanoma Research Jun 2009The objective of this study was to evaluate the antitumor activity and safety profile of 5 mg/m2 plitidepsin administered as a 3-h continuous intravenous infusion every...
The objective of this study was to evaluate the antitumor activity and safety profile of 5 mg/m2 plitidepsin administered as a 3-h continuous intravenous infusion every 2 weeks to patients with advanced malignant melanoma who relapsed or progressed after one line of systemic therapy. Objective response rate (primary efficacy endpoint) was evaluated according to Response Evaluation Criteria In Solid Tumors and toxicity was assessed using National Cancer Institute -Common Toxicity Criteria Version 2.0. Of 39 enrolled patients (median age: 53 years), 37 patients were treated who received a total of 167 treatment cycles (median: 3 cycles per patient; range: 1-32). All patients had received prior systemic therapy with a median of one line per patient (range: 1-6 lines). Of the 35 evaluable patients, two dacarbazine-resistant patients (5.7%) with metastatic cutaneous melanoma achieved partial responses. Five other patients (14.3%) reported stable disease (median stable disease duration: 3.5 months; range: 2.2-15.8 months). Therefore, the rate of tumor growth control was 20.0%. With a median follow-up of 11.0 months, the median progression-free survival was 1.3 months and the median overall survival was 3.5 months. Six patients (16.2%) had the following treatment-related grade 3/4 adverse events: myalgia (n = 3), injection-site reaction (n = 2), hypersensitivity, hypotension, and fatigue (n = 1 each). One patient was withdrawn from the trial because of grade 4 hypersensitivity reaction and hypotension. No severe neutropenia was reported. Plitidepsin showed a minor degree of antitumor activity in patients with refractory advanced malignant melanoma. Further evaluation of plitidepsin in combination schedules may be warranted.
Topics: Adult; Aged; Depsipeptides; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Melanoma; Middle Aged; Neoplasm Recurrence, Local; Peptides, Cyclic; Skin Neoplasms
PubMed: 19436178
DOI: 10.1097/CMR.0b013e32832bbde6