High dose lansoprazole combined with metronomic chemotherapy: a phase i/ii study in companion animals with spontaneously occurring tumors

Spugnini et al. Journal of Translational Medicine 2014, 12:225http://www.translational-medicine.com/content/12/1/225 High dose lansoprazole combined withmetronomic chemotherapy: a phase I/II study incompanion animals with spontaneouslyoccurring tumors Enrico P Spugnini1, Sabrina Buglioni2, Francesca Carocci2, Menicagli Francesco3, Bruno Vincenzi4,Maurizio Fanciulli1 and Stefano Fais5* Background: The treatment of human cancer has been seriously hampered for decades by resistance tochemotherapeutic drugs. A very efficient mechanism of tumor resistance to drugs is the proton pumps-mediatedacidification of tumor microenvironment. Metronomic chemotherapy has shown efficacy in adjuvant fashion as wellas in the treatment of pets with advanced disease. Moreover, we have shown in veterinary clinical settings thatpre-treatment with proton-pumps inhibitors (PPI) increases tumor responsiveness to chemotherapeutics. In thisstudy pet with spontaneously occurring cancer have been recruited to be treated by a combination of metronomicchemotherapy and high dose PPIs and their responses have been matched to those of a historical control of tenpatients treated with metronomic chemotherapy alone.
Methods: Single arm, non randomized phase II open study, with historical control group, evaluating safety andefficacy of the combination of metronomic chemotherapy and alkalization. Twenty-four companion animals(22 dogs and 2 cats) were treated adding to their metronomic chemotherapy protocol the pump inhibitorlansoprazole at high dose, and a water alkalizer. Their responses have been evaluated by clinical and instrumentalevaluation and matched to those of the control group.
Results: The protocol was overall well tolerated, with only two dogs experiencing side effects due to gastrichypochlorhydria consisting with vomiting and or diarrhea. In terms of overall response, in the alkalized cohort,18 out of 24 had partial or complete responses (75%), two patients had a stable disease and the remaining patientsexperienced no response or progressive disease. On the other hand, only one patient in the control groupexperienced a complete response (10%) and three other experienced short lived responses. Median time toterminal event was 34 weeks for the experimental group versus 2 weeks in the controls (p= 0.042).
Conclusions: Patient alkalization has shown to be well tolerated and to increase tumor response to metronomicchemotherapy as well the quality of life in pets with advanced cancer. Further studies are warranted to assess theefficacy of this strategy in patients with advanced cancers in companion animals as well as in humans.
Keywords: Chlorambucil, Cyclophosphamide, Lansoprazole, Piroxicam, Proton pump, Water alkalizer * Correspondence: 5Department of Drug Research and Medicine Evaluation, National Institute ofHealth (ISS), Anti-Tumor Drug Section, Rome, ItalyFull list of author information is available at the end of the article 2014 Spugnini et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver applies to the data made available in this article,unless otherwise stated.
Spugnini et al. Journal of Translational Medicine 2014, 12:225 proposed mechanisms involved in this phenomenon, Cancer initiation, invasion and dissemination are dynamic including decreased uptake or neutralization of weakly phenomena influenced by tumor microenvironment and basic drugs by the acidic tumor microenvironment or the host factors. Standard anticancer drugs were devised ac- confinement of chemotherapy drugs within lysosomal cordingly to Erlich's magic bullet concept and rely on their vesicles . An accelerated turnover of acidic vesicles capacity to directly kill malignant cells. In the attempt to may represent an additional tumor strategy of drug resist- maximize their efficacy, they are administered at a maximal ance based on counteracting current transportation .
tolerated dose (MTD), the highest amount of the drug asso- Recently, a role of nanovesicles (exosomes) released by re- ciated with tolerable toxicity and manageable side effects sistant cancer cells has been in elimination of tumor drug As a consequence of this approach, patients must go such as cisplatin, and extracellular acidity and exosomes through long periods off therapy, allowing for their full re- release belong to a framework exerting a central role of covery from the adverse effects of chemotherapy. These malignant cancer unresponsiveness to chemotherapy interruptions, however, also permit cancer cells to become Interestingly, the expression of proton pumps is increased resistant to chemotherapy and hence to promote a disease in chemoresistant phenotypes and further increased by recurrence As a consequence, despite the discovery of anticancer drugs as well []. Proton pump inhibitors have a significant number of these drugs and the huge number been shown to be highly effective in inhibiting V-ATPases of clinical trials that have been undertaken to develop novel in vitro and well tolerated and effective in murine models, multi-drugs protocols, results has been modest in terms of improving response to chemotherapy and tumor control cure or life extension of cancer patients, especially those []. Moreover, in a previous study, our group showed with advanced-stage or metastatic disease A new thera- that high dose of the proton pump inhibitor lansoprazole peutic paradigm has recently been devised, consisting of could reverse chemoresistance in a cohort of pets affected the use of low-dose chemotherapeutics at short intervals by spontaneous chemoresistant neoplasms, obtaining an (so-called, metronomic chemotherapy), in the absence of high percentage of responders with minimal toxicities extended drug-free periods ]. Metronomic chemother- []. A recent clinical study in osteosarcoma patients has apy is not only almost devoid of toxic effects, but also ex- shown a clear effectiveness of PPI in increasing the effect- erts e direct citotoxicity combined with an antiangiogenic iveness of standard chemotherapy, particularly in those activity resulting in significant efficacy Several studies patients that show low level of responsiveness to the in human and veterinary oncology have shown efficacy of standard protocols []. Thus, the ensemble of these low dose alkylating agents such as cyclophosphamide and studies, but also the evidence that a systemic buffering ap- chlorambucil to directly approach refractory cancers or as proach may represent a useful new strategy in both pre- adjuvant therapy for highly metastatic or metastasizing venting [and in treating cancer, suggested that a tumor The other factor to be taken into account therapy combining different anti-acidic approaches, may when planning a treatment procotol, is the response to represent a real new path in the war against cancer. Thus, chemotherapy by tumor cells. This depends on the con- the aim of this study was to investigate the feasibility, centration of cytostatics accumulated within the cells, tolerability and efficacy of high dose proton pump inhibi- phenomenon that is dependent on functional expression tor lansoprazole combined with water alkalization within of efflux transporters, but also on the pH of extracellular a metronomic protocol in companion animals affected by microenvironment. In fact, the acidity of tumor microenvir- advanced or highly metastatic neoplasms.
onment is a key factor in the low level of responsiveness oftumor cells to chemotherapeutics, and proton exchangers have a crucial impact in extracellular acidification of cancer Patient selection cells Tumor cells rely on H+ exchangers, in particu- Privately owned canine and feline patients with advanced lar the vacuolar H+-ATPases (V-ATPases) to dispose of or highly metastatic neoplasms were selected for the the dangerous protons byproduct of cancer metabolism study. Due to the advanced stage of the disease and the The acidic tumor environment is a consequence of poor response to standard chemotherapy, the owners were anaerobic glucose metabolism resulting in accumulation of offered two options: a) palliative therapy b) metronomic acids such as lactates, leading to enhanced transmembrane chemotherapy with the addition of high dose lansoprazole pH regulation These proton pumps, together with and water alkalization. Their responses have been matched other ion exchangers, play a crucial function in the estab- against those of an historical group of 10 pets treated with lishment and maintenance of cancer microenvironment metronomic chemotherapy alone.
and their action results in the selection of more aggressive Previous informed consent was obtained from the cell phenotypes able to survive in this highly hostile micro- owners. In order to be enrolled in the study, according environment, with a key role in the establishment and to the Italian law (116/92) and the guidelines defined by maintenance of chemoresistance There are several the ethical committee of the National Cancer Institute Spugnini et al. Journal of Translational Medicine 2014, 12:225 "Regina Elena" of Rome, Italy, patients, staged accord- chlorambucil at the dose of 4 mg/m2 and piroxicam at ing to the World Health Organization (WHO) grading the dose of 0.3 mg/kg EOD due to metabolic differences system, were considered eligible if they fulfilled the fol- between the two species and the easier administration of chlorambucil to cats. At presentation patients werevaluated accordingly to a modified Karnofsky performance 1. Normal renal function (normal serum blood urea scale (Table ). Toxicity was defined as disease processes nitrogen [BUN], creatinine, phosphorus, and urine that occurred secondary to therapy and accordingly scored specific gravity).
(Table . Gastro-intestinal toxicity was scored accordingly 2. Absence of underlying life threatening diseases or other medical complications (e.g. diabetes mellitus).
Table 2 Modified Eastern cooperative oncology groupevaluation 3. Compliance of the owner for follow-up rechecks.
4. A presumptive life expectancy of at least four weeks.
Toxicity/Grade signs 5. Overall performance status assessed according to the modified Karnowsky system, had to be less than 3 Staging process included a thorough anamnesis, physical examination, caliper or ultrasonographic measurement of the neoplasm, complete blood cell count (CBC), serumbiochemistry profile, thoracic radiographs (three projections: two laterals and one ventro-dorsal), and abdominal ≤500 neutrophils/mL ultrasonography. In order to confirm the diagnoses, histological re-examination of the biopsies were performed ≥2,500 neutrophils/mL following standard protocols, using Hematoxylin/Eosin and 500–999 neutrophils/mL Experimental approach Dogs and cats with advanced or highly metastaic spon- taneous neoplasms or with chemoresistant tumors Anorexia ≤3 days duration were treated with lansoprazole at the dose of 5 mg/kg Anorexia >3 days but <5 days from Monday through Wednesday and 1 mg/kg from Anorexia ≥5 days 10% weight loss Thursday to Sunday, combined with metronomic chemo-therapy and a commercially available water alkalizer (alka water) added to mineral waters having pH between 7.8 and 8.0 to bring the final water pH to 9. Metronomic chemotherapy consisted with daily cyclophosphamide at Sporadic, self-limiting the dose of 12.5 mg/m2, and piroxicam at the dose of 1–5 episodes per day, <2 days 0.3 mg/kg and was the same for the experimental cohort 6–10 episodes per day, hospitalized and the historical controls . Cats were treated with Table 1 Modified Kamofsky's performance criteria Soft stools, responds to dietary modification Fully active, performs at predisease level 1–4 watery stools per day, <2 days Activity less than predisease level; able to function as 4–7 watery stools per day or >2 days >7 watery stools per day or bloody,hospitalized Severely compromised activity; ambulatory only to point sleeping, and consistently eliminating in acceptable areas.
Completely disabled; must be force fed; unable to defecateor urinate Required medication in acceptable areas Spugnini et al. Journal of Translational Medicine 2014, 12:225 to the Veterinary Comparative Oncology Group guidelines for highly metastatic tumors, following PPI and [In order to have the best assessment of therapy chemotherapy for a defined period of time.
toxicoses, after every therapy owners were sent home witha questionnaire to be completed in order to record pos- Statistical analysis sible gastrointestinal side effects of the protocol (Table ).
Response to treatment was assessed using the median Response to treatment was assessed on the basis of clinical time to terminal event and its 95% confidence interval.
evaluation and confirmatory biopsies. Response to treat- The terminal event was tumor progression, recurrence or ment in terms of toxicity and tumor response were assessed death attributable to cancer or other non-cancer causes.
prior each therapy. At that time a physical exam and tumor Time to recurrence was defined as time from the observa- measure were performed. Moreover thoracic radiographs tion of tumor disappearance and estimated according to the and abdominal ultrasonography were performed every two Kaplan-Meier method . The statistical significance of months to check for tumor spread. Tumor response was the differences in survival distribution among the treatment defined as follows: groups (experimental versus control) was evaluated by thelog-rank test . P values <0.05 were regarded as signifi- Complete Remission (CR) - the disappearance of all cant in two-tailed tests. SPSS software (version 10.00 SPSS evidence of cancer in all sites for a defined period of time.
Chicago) was used for statistical analysis.
Partial Remission (PR) - the decrease in size of alltumors by 50% or greater as measured by the sum of Evaluation of patients the product of two diameters of each tumor for a Finally, the owners were questioned prior to each therapy defined period of time.
on the activity level, performance status and food and water Stable Disease (SD) - the decrease of <50% or an consumption of their animals. Patients had a complete increase of < 25% in the sum of the product of two hematological and biochemical analysis performed every diameters for a defined period of time.
two weeks, while thoracic radiographs and ultrasonogra- Progressive Disease (PD) - the increase of 25% or pic exam were scheduled to be performed at 1, 3, 5, 7, 9, more in the sum of the product of two diameters for a 12, 18 months, together with a physical evaluation. More- defined period of time.
over, owner have been interviewed regarding their degree No evidence of disease – absence of tumor growth of satisfaction regarding the treatments. This was made as (local recurrence or distant metastases) after surgery a surrogate for the psychological aspects of chemotherapy Table 3 Daily evaluation form sent home and made out by the owners 3 episodes per day 5 episodes per day >5 episodes per day days lasting >4 days and vomiting lasting 2 days vomiting lasting 4 days >6 more stools Appetite loss with Salivating or lip Salivation or lip normal eating habits smacking for 12 hrs smacking for 24 hrs smacking >24 h With treats or diet Appetite loss for 3 days OR Appetite loss for 5 days OR With treats or diet With treats or diet change, ate 50% of normal change, ate few bites 1-2 episodes per day 2-4 episodes per day 4-6 episodes per day > 6 episodes per day Moderate lethargy, difficulty Severe lethargy, only with daily activities gets up to go outside Spugnini et al. Journal of Translational Medicine 2014, 12:225 in human patients as well as to assess quality of life during Patients characteristics and response to therapy are shown the treatment. Indeed, while Treatment were scheduled to in Table . Eight patient had previous surgery for their pri- be continued until a complete remission or an absence of mary tumors (six of them had either regional metastases disease was observed for one year, a maintenance schedule or local recurrence when referred for therapy) and one had was devised for the long term responders. At that time three sessions of electrochemotherapy resulting in partial chemotherapy was discontinued while therapy with lanso- remission of the tumor. This last patient then switched to prazole and patient alkalization were continued as a main- metronomic chemotherapy for financial reasons and tenance protocol.
further improved the tumor response. None of the pa-tients with metastatic disease had metastasectomy per- formed prior to referral, having all the owners elected Twenty-four pets affected by different solid tumors were their pets to be pharmacologically treated. The only enrolled in the study (twenty-two dogs and two cats) patients that has no evidence of disease at the time of over a 30 months period. There were 11 male dogs and referral were four patients with ruptured splenic heman- 11 female dogs, most of whom where spayed while the giosarcoma (two per each cohort) that have been enrolled two cats were both female. Age ranged from 6 to 13 years.
in the survival study in consideration of the extremely high Table 4 Patients characteristics and outcome of 24 pets with advanced cancer treated with metronomic chemotherapyand alkalization Metastatic Anal sac Ca (sublumbar lymph nodes) Metastatic Anal sac Ca (sublumbar lymph nodes) Labrador retriever Recurring inflammatory mammary Ca Recurring inflammatory mammary Ca Metastatic mammary Ca (axillary lymph node) Labrador retriever Visceral histiocytosis Recurring anaplastic mammary carcinoma The tumor stage refers at the moment of referral. HSA patients were referred after the surgical removal of their ruptured spleen and were the only patientswithout gross disease.
Abbreviations: CA carcinoma, CR complete remission, CSA chondrosarcoma, F female, FS female spayed, M male, MC male castrated, NED no evidence of disease,OSA osteosarcoma, PD progressive disease, PR partial remission, SCC squamous cell carcinoma, SD stable disease.
Spugnini et al. Journal of Translational Medicine 2014, 12:225 metastatic tendency of this neoplasm in the canine popu- 37.5% while only one control patient is still alive with a sur- lation. All the four patients begun their medical therapy vival rate of 10%. The mean time to terminal event was two weeks after splenectomy. Survival time was calculated 48 weeks in the experimental cohort and 18 weeks in the from the beginning of metronomic chemotherapy. The control group, median time to terminal event was 34 weeks historical control group consisted with 10 dogs affected by versus 2. Figure shows the Kaplan-Meier survavial curve different neoplasms whose characteristics are summarized for the two groups. In general, the owners of the experi- in Table In this group there were 6 females and 4 males mental group reported increased activity level as well as who tolerated the metronomic therapy without side effects.
food and water consumption and improved quality of life.
The combination of metronomic chemotherapy and alkal- Questioning the owners regarding their degree of satisfac- izing treatment was overall well tolerated, one dog had mild tion with the outcome of the therapy yielded a total of 90% diarrhea but continued the therapy albeit at a decreased of appreciation in the PPI group and a 40% in the control lansoprazole dose (2 mg/kg in the three loading days).
group. Appreciation was greatly influenced on the pets Two dogs had vomiting that resulted in lansoprazole re- moving up in the karnofsky scale as a consequence of im- duction from 5 mg/kg to 3 mg/kg. Finally 8 dogs out of proved response and degree of side effects and ranged from 22 experienced different degrees of flatulence that par- "somewhat satisfied" to "enthusiastic". Figure summarizes tially improved with the addition of probiotics to their the degree of satisfaction among the different groups of diet. The overall responses rate was 75%, including 4 owners. While tumor control was the major issue in the complete remissions, 10 partial responses, 4 no evidence control group, in the PPI cohort, as a consequence of a bet- of disease (adjuvant therapy group), 2 stable diseases and ter clinical outcome, the major causes of complains were 4 progressive diseases. On the other hand, the overall the gastrointestinal side effects (specifically the flatulence) response rate in the control group was 40% with two experienced by some dogs rather than the degree of tumor short lived NEDs in dogs with highly metastatic cancers, response. The management of these complications through one PR in a dog with a ulnar OSA that recurred after par- diet and integration with probiotics greatly improved the tial ulnectomy and one long lasting CR in a dog with an owners degree of satisfaction.
inflammatory mammary carcinoma. In this cohort only onepatient out of ten experienced a complete long lasting re- sponse, while all the other were non responders or short The proton pump inhibitor lansoprazole, administered at lived responders. Figure shows two patients that success- high dose and combined with a water alkalizer, has proven fully responded to the therapy while Figure shows a stable to enhance tumor response to metronomic chemotherapy, disease in a dog with a large lung tumor. At the time of increasing the number of complete responders and writing a total of 9 patients (8 dogs and 1 cat) are still alive significantly delaying the onset of metastases in pets with and periodically monitored leading to a survival rate of highly metastasizing neoplasms. This is a very promising Table 5 Patients characteristics and outcome of 10 pets with advanced cancer treated with metronomic chemotherapy alone Anal sac Ca (sublumbar lymph nodes) Inflammatory mammary Ca Inflammatory mammary Ca Anaplastic mammary Ca (axillary lymph node) Abbreviations: CA carcinoma, CR complete remission, F female, FS female spayed, M male, MC male castrated, NED no evidence of disease, OSA osteosarcoma,PD progressive disease, PR partial remission.

Spugnini et al. Journal of Translational Medicine 2014, 12:225 Figure 1 A canine patient with a nasal sarcoma at presentation (A) and after 4 months of therapy (B), the dog had a nasal sinussarcoma that underwent PR resulting in cessation of nasal discharge and bleeding as well as pawing at the lesion. Another patient witha large ulcerated high grade mammary carcinoma (C) experiencing a long lasting PR (D).
result, since a "flaw" of metronomic chemotherapy is the study presented tumors that very often varied in their his- low number of patients experiencing complete responses tologies. Moreover, the owners of the pets affected with as well as the difficulty to have a significant delay for the advanced cancer were particularly available in trying new onset of metastatic disease in patients with advanced can- approached being well aware of the disease in their cer ]. The broad spectrum of solid tumors that companion animals and of their expected poor progno- responded to this clinical approach including two patients sis. Notably, although the level of cancer progression with metastasized anal sac carcinoma makes this combin- and the size of the cancer, we observed a clear improve- ation extremely promising. Of course this study had some ment of the clinical response to the metronomic therapy limitations due to the lack of tumor homogeneity in our when combined with an alkalinizing treatment, inde- two cohorts. This bias can't be overcome, inasmuch pets pendently from the nature of cancer, suggesting that with advanced cancer stage suitable to be included to this systemic alkalinisation might represent one of the most Figure 2 A canine patient with lung cancer treated with metronomic chemotherapy and alkalization at presentation (A) and at fourmonths control (B).

Spugnini et al. Journal of Translational Medicine 2014, 12:225 Figure 3 Kaplan-Meier survival curve for alkalized patients (red line) and controls (blue line).
Figure 4 Histogram representation of the owners' percentage and degree of satisfaction for the clinical outcome of their pets in thePPI and control groups.
Spugnini et al. Journal of Translational Medicine 2014, 12:225 important new implementation in cancer therapy, inas- response of the body against cancer. Further investigations much as tumor extracellular acidity is a feature com- are clearly warranted also in this perspective to assess the mon to all cancers. This is for sure a novelty in the weight of the immune component in the long term control clinical management of cancer patients that should be of tumors in patient undergoing alkalizing metronomic taken into careful account in the future anti-cancer strategies. Of course our study lacked a system to assess Competing interests the in vivo pH changes as well; this was due to the absence The authors declare that they have no competing interests.
of pH measurement methodology approved for theclinical use but also to the financial constrains to an Authors' contributions observational setting. In order to improve the protocol All the authors read and approved the final manuscript. EPS participated inthe study design and coordinated the clinicians involved in the trial, SB and and to identify prognostic factors, steps should be made FC helped with the clinical management of the patients, FM coordinated the to measure changes in tumor pH during the therapy in imaging studies of the investigation, BV elaborated the statistical analysis, MF order to monitor progresses and also to have a param- helped with to devise the study, SF participated in the study design andcoordinated the different units.
eter to be monitored in order to identify escape frommedical control. Furthermore, a reliable and portable system to quantify variation in growth factors involved This work has been supported by a Grant of the Italian Ministry of Health to SF.
in tumor progression and angiogenesis should be devised []. The combination of water alkalinisation and high 1SAFU Department, Regina Elena Cancer Institute, Rome, Italy. 2Ambulatorio dosage proton pump inhibitors has been shown to effect- Veterinario "Le Accademie", Rome, Italy. 3Centro Veterinario Gianicolense,Rome, Italy. 4Università Campus Biomedico, Rome, Italy. 5Department of Drug iveness of metronomic therapy on tumour progression, Research and Medicine Evaluation, National Institute of Health (ISS), but also to highly improve the quality of life of pets affected Anti-Tumor Drug Section, Rome, Italy.
by spontaneous malignant tumors. In particular the animals Received: 28 April 2014 Accepted: 4 August 2014 did not show to refuse the alkalinized water, while occa- Published: 21 August 2014 sional experience in human patients showed that sodiumbicarbonate may not be administered for a long period of Chen Z, Cui Y, Owonikoko TK, Wang Z, Li Z, Luo R, Kutner M, Khuri FR, time, inasmuch as patients very often refused it. Notably, Kowalski J: Escalation with overdose control using all toxicities and time while this study allowed to try with a real experimental clin- to event toxicity data in cancer phase I clinical trials. Contemp Clin Trials ical approach against advanced cancer, it did not allow to 2014, Epub ahead of print.
Jang SH, Wientjes MG, Lu D, Au JLS: Drug delivery and transport to solid quantify the exact contribution of PPIs and alkalized water tumors. Pharm Res 2003, 20:1337–1350.
to the increased efficacy of metronomic chemotherapy, Kim JJ, Tannock IF: Repopulation of cancer cells during therapy: an while alkalinizing approaches using sodium bicarbonate important cause of treatment failure. Nat Rev Cancer 2005, 5:516–25.
Davis AJ, Tannock JF: Repopulation of tumour cells between cycles of suggest a potential efficacy of water alkalinisation in cancer chemotherapy: a neglected factor. Lancet Oncol 2000, 1:86–93.
treatment [Further studies will be mandatory to evalu- Kerbel RS, Kamen BA: The anti-angiogenic basis of metronomic chemotherapy.
ate the effects of single alkalinizing approaches as potential Nat Rev Cancer 2004, 4:423–36.
Gasparini G: Metronomic scheduling: the future of chemotherapy? Lancet anti-cancer treatments . In our study the owners of the pet Oncol 2001, 2:733–40.
included in the experimental group provided the emotional Mross K, Steinbild S: Metronomic anti-cancer therapy – an ongoing component and a daily evaluation of the quality of life, pro- treatment option for advanced cancer patients. J Canc Res Therapeut2012, 1:32.
viding a rough estimate of the patient toleration of the Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS, Folkman therapeutic regimen, allowing the investigators to work in a J: Antiangiogenic scheduling of chemotherapy improves efficacy against close approximation of the human clinical condition. More- experimental drug-resistant cancer. Cancer Res 2000, 60:1878–86.
Sheng Sow H, Mattarollo SR: Combining low-dose metronomic chemotherapy over, sodium bicarbonate is an unbalanced buffer with only with anticancer vaccines: a therapeutic opportunity for lymphomas.
sodium as an oligoelement, and this may raise cardiovascu- Oncoimmunology 2013, 2:e27058.
lar problems in long term administrations. The inclusion of Adenis A, Ray-Coquard I, Italiano A, Chauzit E, Bui-Nguyen B, Blay JY,Tresch-Bruneel E, Fournier C, Clisant S, Amela EY, Cassier PA, Molimard multiple drugs affecting tumor acidity is highly desirable in M, Penel N: A dose-escalating phase I of imatinib mesylate with fixed order to develop multidrug protocols to increase cancer dose of metronomic cyclophosphamide in targeted solid tumours.
control Finally, there is accumulating evidence also in- Br J Cancer 2013, 109:2574–8.
Robison NJ, Campigotto F, Chi SN, Manley PE, Turner CD, Zimmerman MA, dicating that some metronomic regimens might be able to Chordas CA, Werger AM, Allen JC, Goldman S, Rubin JB, Isakoff MS, Pan WJ, promote disease eradication by stimulating anticancer im- Khatib ZA, Comito MA, Bendel AE, Pietrantonio JB, Kondrat L, Hubbs SM, mune and selectively eliminating immunosuppressive cells Neuberg DS, Kieran MW: A phase II trial of a multi-agent oral antiangiogenic(metronomic) regimen in children with recurrent or progressive cancer.
The increased anti-tumor immune response by pro- Pediatr Blood Cancer 2014, 61:636–42.
ton pump inhibitors has been clearly shown and Lana S, U'ren L, Plaza S, Elmslie R, Gustafson D, Morley P, Dow S: the overall response to the combination of proton pump in- Continuous low-dose oral chemotherapy for adjuvant therapy of splenichemangiosarcoma in dogs. J Vet Intern Med 2007, 21:764–9.
hibitors, alkalinized water and metronomic therapy, suggest Leach TN, Childress MO, Greene SN, Mohamed AS, Moore GE, Schrempp that this approach may be highly helpful in the generalized DR, Lahrman SR, Knapp DW: Prospective trial of metronomic chlorambucil Spugnini et al. Journal of Translational Medicine 2014, 12:225 chemotherapy in dogs with naturally occurring cancer. Vet Comp Oncol Huber V, De Milito A, Harguindey S, Reshkin SJ, Wahl ML, Rauch C, Chiesi A, 2012, 10:102–12.
Pouysségur J, Gatenby RA, Rivoltini L, Fais S: Proton dynamics in cancer.
Schrempp DR, Childress MO, Stewart JC, Leach TN, Tan KM, Abbo AH, de J Transl Med 2010, 8:57.
Gortari AE, Bonney PL, Knapp DW: Metronomic administration of Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A, Ricupito A, Cova A, chlorambucil for treatment of dogs with urinary bladder transitional cell Canese R, Jachetti E, Rossetti M, Huber V, Parmiani G, Generoso L, Santinami M, carcinoma. J Am Vet Med Assoc 2013, 242:1534–8.
Borghi M, Fais S, Bellone M, Rivoltini L: Modulation of microenvironment Mitchell L, Thamm DH, Biller BJ: Clinical and immunomodulatory effects of acidity reverses anergy in human and murine tumor-infiltrating T toceranib combined with low-dose cyclophosphamide in dogs with lymphocytes. Cancer Res 2012, 72:2746–56.
cancer. J Vet Intern Med 2012, 26:355–62.
Elmslie RE, Glawe P, Dow SW: Metronomic therapy with cyclophosphamide and piroxicam effectively delays tumor recurrence in Cite this article as: Spugnini et al.: High dose lansoprazole combined dogs with incompletely resected soft tissue sarcomas. J Vet Intern Med with metronomic chemotherapy: a phase I/II study in companion 2008, 22:1373–9.
animals with spontaneously occurring tumors. Journal of Translational Marchetti V, Giorgi M, Fioravanti A, Finotello R, Citi S, Canu B, Orlandi P, Di Medicine 2014 12:225.
Desidero T, Danesi R, Bocci G: First-line metronomic chemotherapy in ametastatic model of spontaneous canine tumours: a pilot study. InvestNew Drugs 2012, 30:1725–30.
De Milito A, Fais S: Tumor acidity, chemoresistance and proton pumpinhibitors. Future Oncol 2005, 1:779–86.
Fais S: Proton pump inhibitor-induced tumour cell death by inhibition ofa detoxification mechanism. J Intern Med 2010, 267:515–25. Fais S, DeMilito A, You H, Qin W. Targeting vacuolar H+-ATPases as a new strategyagainst cancer. Cancer Res 2007; 67: 10627–10630.
Cipriano DJ, Wang Y, Bond S, Hinton A, Jefferies KC, Qi J, Forgac M:Structure and regulation of the vacuolar ATPases. Biochim Biophys Acta2008, 1777:599–604.
Jefferies KC, Cipriano DJ, Forgac M: Function, structure and regulation ofthe vacuolar (H+)-ATPases. Arch Biochem Biophys 2008, 476:33–42.
Spugnini EP, Citro G, Fais S: Proton pump inhibitors as anti vacuolar-ATPasesdrugs: a novel anticancer strategy. J Exp Clin Cancer Res 2010, 29:44.
Murakami T, Shibuya I, Ise T, Chen ZS, Akiyama S, Nakagawa M, Izumi H,Nakamura T, Matsuo K, Yamada Y, Kohno K: Elevated expression ofvacuolar proton pump genes and cellular PH in cisplatin resistance.
Int J Cancer 2001, 93:869–874.
De Milito A, Iessi E, Logozzi M, Lozupone F, Spada M, Marino ML, Federici C,Perdicchio M, Matarrese P, Lugini L, Nilsson A, Fais S: Proton pumpinhibitors induce apoptosis of human B-cell tumors through acaspase-independent mechanism involving reactive oxygen species.
Cancer Res 2007, 67:5408–17.
Federici C, Petrucci F, Caimi S, Cesolini A, Logozzi M, Borghi M, D'Ilio S,Lugini L, Violante N, Azzarito T, Majorani C, Brambilla D, Fais S: Exosomerelease and low pH belong to a framework of resistance of humanmelanoma cells to cisplatin. PLoS One 2014, 9:e88193.
Spugnini EP, Baldi A, Buglioni S, Carocci F, Milesi de Bazzichini G, Betti G,Pantaleo I, Menicagli F, Citro G, Fais S: Lansoprazole as a rescue agent inchemoresistant tumors: a phase I/II study in companion animals withspontaneously occurring tumors. J Transl Med 2011, 9:221.
Ferrari S, Perut F, Fagioli F, Brach Del Prever A, Meazza C, Parafioriti A, PicciP, Gambarotti M, Avnet S, Baldini N, Fais S: Proton pump inhibitorchemosensitization in human osteosarcoma: from the bench to thepatients' bed. J Transl Med 2013, 11:268.
Ibrahim-Hashim A, Cornnell HH, Abrahams D, Lloyd M, Bui M, Gillies RJ,Gatenby RA: Systemic buffers inhibit carcinogenesis in TRAMP mice.
J Urol 2012, 188:624–31.
Robey IF, Baggett BK, Kirkpatrick ND, Roe DJ, Dosescu J, Sloane BF, HashimAI, Morse DL, Raghunand N, Gatenby RA, Gillies RJ: Bicarbonate increasestumor pH and inhibits spontaneous metastases. Cancer Res 2009,69(6):2260–8.
Submit your next manuscript to BioMed Central
Chretin JD, Rassnick KM, Shaw NA, Hahn KA, Ogilvie GK, Kristal O, Northrup and take full advantage of:
NC, Moore AS: Prophylactic trimethoprim-sulfadiazine duringchemotherapy in dogs with lymphoma and osteosarcoma: a double-blind, • Convenient online submission
placebo-controlled study. J Vet Intern Med 2007, 2(1):141–8.
Kaplan EL, Meier P: Nonparametric estimation from incomplete • Thorough peer review
observations. J Am Stat Assoc 1958, 53:457–481.
• No space constraints or color figure charges
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, Mantel N,McPherson K, Peto J, Smith PG: Design and analysis of randomized clinical • Immediate publication on acceptance
trials requiring prolonged observation of each patient: II analysis and • Inclusion in PubMed, CAS, Scopus and Google Scholar
examples. Br J Cancer 1977, 35:1–39.
• Research which is freely available for redistribution
Robey IF, Martin NK: Bicarbonate and dichloroacetate: evaluating pHaltering therapies in a mouse model for metastatic breast cancer.
BMC Cancer 2011, 11:235.
Submit your manuscript at www.biomedcentral.com/submit

Source: http://www.medicinenaturali.net/cancro/acidosi_cancro_Fais_spugnini_JTM_2014_english.pdf

Historia de la concordia

RECOPILACIÓN HISTÓRICA DE CONCORDIA Luis María Medina PALABRAS INICIALES (primera edición 1977) Esta no es una historia de Concordia. Apenas si pretende ser una cronología de hechos, en la mayoría de los casos ya publicados. Es por ello que hasta el título de este trabajo aspira a ilustrar claramente al lector sobre el contenido del mismo. Consideramos que este trabajo es, simplemente, una recopilación histórica de nuestra ciudad. Desde fines del año 1969 y hasta principios de 1971, apareció en Concordia una revista semanal –"La Calle"- que incluyó en cada número una sección destinada a hacer conocer hechos y personas del pasado de nuestra ciudad. Volvieron del ayer, entonces, páginas agotadas de la historia lugareña, lo que contó con la aceptación unánime de los lectores. Esa labor se vio respaldada ampliamente, lográndose la colaboración espontánea de numerosos vecinos que aportaron revistas, libros, documentos y recuerdos, material que tuvo cabida en cada número de la citada publicación. Aparecieron también historiadores locales que volcaron sus estudios y conocimientos a la difusión general de un tema tan interesante. "La Calle" se transformó, entonces, en el medio más adecuado para hacer conocer retazos de la historia concordiense. GRAFELCO hoy puede ofrecer una recopilación cronológica de todo ese material, llenando algunos vacíos lógicos con el fruto de sus consultas en otras fuentes no directamente relacionadas con esta ciudad. Sin embargo, quedan aún muchos claros. Es por ello que reiteramos que ésta no es la historia de Concordia. No obstante, puede convertirse en el motivo fundamental para escribirla definitivamente, corrigiendo errores que seguramente existen en esta edición. Conocemos la labor silenciosa de algunos estudiosos de nuestro medio, que vienen gestando, desde mucho tiempo atrás, una obra de esta naturaleza. Y aunque no ignoramos que, además del tiempo que demanda dicha tarea, también deberán vencer el problema de su publicación –que malogra muchas veces las mejores inquietudes- aspiramos a que la presente sirva de acicate para quienes están empeñados en una obra similar. A ellos les auguramos el mayor de los éxitos. GRAFELCO


How were new medicines discovered?David C. Swinney*‡ and Jason Anthony* Abstract Preclinical strategies that are used to identify potential drug candidates include target-based screening, phenotypic screening, modification of natural substances and biologic-based approaches. To investigate whether some strategies have been more successful than others in the discovery of new drugs, we analysed the discovery strategies and the molecular mechanism of action (MMOA) for new molecular entities and new biologics that were approved by the US Food and Drug Administration between 1999 and 2008. Out of the 259 agents that were approved, 75 were first-in-class drugs with new MMOAs, and out of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of first-in-class small-molecule drugs exceeded that of target-based approaches — with 28 and 17 of these drugs coming from the two approaches, respectively — in an era in which the major focus was on target-based approaches. We postulate that a target-centric approach for first-in-class drugs, without consideration of an optimal MMOA, may contribute to the current high attrition rates and low productivity in pharmaceutical research and development.