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14 janauri 2017: Bron: Verschillende studies uit Pubmed

Monoterpene Perillyl Alcohol geeft uitstekende resultaten bij hersentumoren en ook bij uitzaaiingen in de hersenen vanuit andere vormen van kanker. Maar vooral was het effect opvallend groot bij hersentumoren (glioma's) van het type astrocytomen en een recidief van een glioblastoma werd de progressievrije ziektetijd sterk vergroot, Bij de laatste groep bereikte Perillyl alcohol een nagenoeg verdubbeling van de progressievrije tijd in vergelijking met resultaten uit eerdere studies als controlegroepen gehaald uit bestaande literatuur.

Uit een laatste studie bleek dat 19% van de patienten met een recidief van een Glioma Blastoma op basis van alleen POH - Monoterpene Perillyl Alcohol nog steeds na 4 jaar in leven zijn.

Dit is de conclusie uit een recent studierapport (december 2016) in het Engels maar verderop in dit artikel beschrijf en vertaal ik de belangrijkste gegevens in het Nederlands enz.

In conclusion,

  • (a) long-term POH inhalation was a safe and noninvasive therapeutic strategy for malignant gliomas;
  • (b) long-term POH inhalation consistently improved survival of patients with grade III and grade IV AA with oligodendroglia component;
  • c) patients with secondary GBM had a better response to POH inhalation than patients with primary GBM; (d) 19% of recurrent malignant glioma patients still remain in clinical remission after 4 years under exclusive POH inhalation treatment;
  • (e) long-term POH inhalation did not cause any evident clinical and /or laboratory-based toxicity.
  • We can envisage in a near future the synthesis of biologically-active hybrid molecules containing POH as a carrier conjugated to drugs specifically targeting critical regulators of cell proliferation, as a promising antitumor therapeutic strategy successfully employed to treat brain tumors.

Bv. uit een studie met 89 patiënten met een recidief van een hersentumor van het type glioblastoma die werden behandeld met een neusspray van POH (Monoterpene Perrlyl Alcohol) werd vergeleken met een controlegroep van 52 patiënten met primaire Glioblastoma maar die geen behandeling meer hadden gekregen maar alleen ondersteunende palliatieve hulp omdat de kanker al te ver was doorgedrongen.

Foto laat een man zien die via een neusspray de POH binnen krijgt. Tekst gaat onder foto verder

Perellyl alcohol - POH man met neusspray

De patiënten met een recidief van een primaire Glioblastoma die alleen daarna met POH werden behandeld leefden met de neusspray met POH (Monoterpene Perrlyl Alcohol) mediaan gemeten 11.2 maanden, langer (log rank test, P = 0.0366) dan de patienten uit de Glioblastomagroep met een primaire status die mediaan 5.9 maanden leefden na de start van de studie. Opvallend was dat POH het beste werkte bij patiënten met een dieper in de hersenstam doorgedrongen tumorcellen dan die waarbij de tumor nog minder ver was doorgedrongen in de hersenen. Vermindering van corticosteroiden (36%) blijkt gerelateerd aan langzamere progressie van de ziekte. 

De bijwerkingen van POH (Monoterpene Perrlyl Alcohol) als neusspray toegediend zijn nagenoeg nihil. 1 patiënt uit deze studie overleeft al 5 jaar haar hersentumor met alleen POH als medicijn. Zie haar studierapport als case studie gepubliceerd: 

Case of Advanced Recurrent Glioblastoma Successfully Treated with Monoterpene Perillyl Alcohol by Intranasal Administration

Intranasale POH (Monoterpene Perrlyl Alcohol) bevordert duurzame overall overleving van een recidief van een Glioma Blastoma 

Hieronder beelden van deze vrouw haar scans. In het studierapport staan er meer.

Tekst gaat onder beeld verder.

Brain MRI done in October 2009 still revealed irregular

(a)(b)

Figure 1. MRI brain image of recurrent GBM before and after POH intranasal administration. Note the decrease in tumor size between the initial MRI ((a); (d)) at the time of inclusion in POH protocol, images obtained in August 2008 ((b); (e)) and performed after 4 years and 9 months ((c) and (f)) of daily treatment with POH by intranasal route.

In een andere Fase I/II studie werd POH (Monoterpene Perrlyl Alcohol) via een neusspray toegediend bij patiënten met een recidief van een kwaadaardige glioma nadat zij vooraf waren behandeld met operatie, radiotherapie - bestraling en chemotherapie (Temozomide - Temodal). De POH werd toegediend in een concentratie van 0.3% volume/volume (55 mg) 4 keer per dag in een onderbroken schema.

De studiegroep bestond uit 37 patiënten, 29 patiënten met een glioblastoma multiforme (GBM), 5 met een astrocytoom graad III (AA), en 3 met een anaplastisch oligodendroglioma (AO).

Het objectieve doel van deze studie was de toxiciteit en de progressievrije tijd (PFS) te meten 6 maanden na de start van de behandeling. Neurologisch onderzoek en CT scans en MRI-scans zouden ziekteprogressie moeten vaststellen en bevestigen. Een CR = Complete remissie (response) werd gedefinieerd als neurologisch stabiel of verbetering van de conditie, geen zichtbare actieve tumoren meer op een CT/MRI scan en het niet meer nodig hebben van corticosteroiden (o.a. dexamethason is een van de meest gebruikte corticostiroiden);
Een PR = partiële remissie - response werd gedefinieerd als gelijk of meer dan 50% vermindering van tumoromvang op een CT/MRI scan, neurologische stabiliteit of verbetering van de conditie en geen gebruik meer van corticosteroiden;
PC = Progressieve ziekte (PC) werd gedefinieerd als gelijk of minder dan 25% vermindering van tumorvolume op een CT/MRI scan en het verschijnen van nieuwe tumoren. 
SD = Stabiele ziekte werd gedefinieerd als er geen sprake was van verandering in progressie van de ziekte, noch in tumoromvang op een CT/MRI scan noch in neurologische status.

De resultaten uit deze studie:

Na 6 maanden behandeling zoals in de doelen geformuleerd:

Een PR - partiële remissie werd gezien bij 3.4% (n=1) van de patienten met een Glioblastoma en 33.3% (n=1) bij patiënten met een anaplastisch oligodendroglioma (AO);
SD - stabiele ziekte 44.8% (n=13) bij patienten met een Glioblastoma (GBM), 60% (n=3) bij patiënten met een Astrocytoom (AA), en 33.3% (n=1) bij patiënten met een anaplastisch oligodendroglioma (AO); 

PC - progressieve ziekte werd vastgesteld bij 51.7% (n=15) van de patiënten met een Glioblastoom (GBM), 40% (n=2), bij patiënten met een Astrocytoom (AA) en 33.3% (n=1) bij patiënten met een anaplastisch oligodendroglioma (AO).

PFS = Progressievrije ziekte of SD = Stabiele ziekte werd gezien bij 48.2% (n = 14) van de patiënten met een Glioblastoma (GBM), 60% (n = 3) bij patiënten met een Astrocytoom (AA), en 66.6% (n = 2) bij patiënten met een anaplastisch oligodendroglioma (AO).

Conclusie:

De onderzoekers van deze studie concluderen hetzelfde als de onderzoekers uit de eerdere studie namelijk: deze resultaten suggereren dat intra nasale toediening van POH (Monoterpene Perrlyl Alcohol) een veilige en niet invasieve goedkope behandeling is. Er waren geen meldingen van toxiciteit en de regressie van de tumoren bij sommige patiënten suggereert dat POH ook een anti tumor effectiviteit heeft. 

In een andere case studie wordt het verloop van de ziekte bij een patiënt - een blanke vrouw van 51 jaar -  met een recidief van een Glioblastoma beschreven. Deze patient gebruikte POH naast voortdurende temozomide (Temodal): Perillyl alcohol inhalation concomitant with oral temozolomide halts progression of recurrent inoperable glioblastoma: a case report

Hier een scanbeeld van de vrouw: tekst gaat verder onder beeld:

Perellyl alcohol - POH vrouw van 51 jaar

Op het moment van publicatie van haar case studie i december 2014 was de vrouw nog steeds kankervrij:

From December 2012 up to now (December 2014), the patient has remained in good health under exclusive POH inhalation therapy combined with TMZ schedule, without any evidence of tumor recurrence, and only taking anti-seizure medication but no steroidal drugs. Recent clinical laboratory analysis showed hematologic and biochemical parameters within normal range values, without any signs of neurologic, hepatic and renal toxicity or clinical adverse effects.

Het zal duidelijk zijn dat POH (Monoterpene Perrlyl Alcohol) met grote interesse wordt gevolgd in de wetenschappeljike wereld. Afgelopen week vroeg een patiente met een recidief van een Glioblastoma die afgelopen week is begonnen bij dr. Stefaan van Gool met een behandeling met immuuntherapie of ik dit middel kende want dr. van Gool had haar dit aanbevolen. Toevallig was ik net bezig met dit artikel dus heb haar nu ook dit allemaal toegestuurd.

Perrilyl Alcohol is een zogeheten RAS remmer, een natuurlijk niet toxisch middel dat gewonnen - geisoleerd wordt uit verschillende oliën uit verschillende planten en kruiden en fruit zoals citrusvruchten, kersen, lavendel, pepermunt, groene munt, veenbessen, gember en citroengras o.a. en als zodanig door een apotheker moet worden samengesteld.

Op deze website staat veel gedetailleerde informatie over POH (Monoterpene Perrlyl Alcohol) waarvan ik een en ander heb gebruikt voor bovenstaand artikel.

Andere studierapporten die ik gebruikt heb naast de al vernoemde zijn:

Ras pathway activation in gliomas: a strategic target for intranasal administration of perillyl alcohol

en

Perillyl alcohol and methyl jasmonate sensitize cancer cells to cisplatin

en

Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation.

en

Correlation of tumor topography and peritumoral edema of recurrent malignant gliomas with therapeutic response to intranasal administration of perillyl alcohol

en

Intranasal Administration of Perillyl Alcohol Activates Peripheral and Bronchus-Associated Immune System In Vivo

en

Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases

en

Monoterpene as a chemopreventive agent for regression of mammalian nervous system cell tumors, use of monoterpene for causing regression and inhibition of nervous system cell tumors, and method for administration of monoterpene perillyl alcohol


Hieronder de abstracten van Long-term outcome in patients with recurrent malignant glioma treated with Perillyl alcohol inhalation

en van 

Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases

Met referentielijsten

From the large field of drug modifications aimed at the enhancement of BBB penetration, we presented NEO212, where temozolomide, a sub-optimally brain-targeting molecule, was conjugated to POH. Based on in silico prediction, as well as preclinical brain tumor and brain metastasis models, NEO212 appears to be a novel compound with great therapeutic promise.

Int J Mol Sci. 2016 Sep; 17(9): 1463.
Published online 2016 Sep 2. doi:  10.3390/ijms17091463
PMCID: PMC5037741

Perillyl Alcohol and Its Drug-Conjugated Derivatives as Potential Novel Methods of Treating Brain Metastases

Thomas C. Chen,1 Clovis O. Da Fonseca,2 and Axel H. Schönthal3,*
Dario Marchetti, Academic Editor
Author information ► Article notes ► Copyright and License information ►
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Abstract

Metastasis to the central nervous system remains difficult to treat, and such patients are faced with a dismal prognosis. The blood-brain barrier (BBB), despite being partially compromised within malignant lesions in the brain, still retains much of its barrier function and prevents most chemotherapeutic agents from effectively reaching the tumor cells. Here, we review some of the recent developments aimed at overcoming this obstacle in order to more effectively deliver chemotherapeutic agents to the intracranial tumor site. These advances include intranasal delivery to achieve direct nose-to-brain transport of anticancer agents and covalent modification of existing drugs to support enhanced penetration of the BBB. In both of these areas, use of the natural product perillyl alcohol, a monoterpene with anticancer properties, contributed to promising new results, which will be discussed here.

4. Conclusions and Outlook

Over the past decade, better control of systemic neoplastic disease has resulted in prolonged survival of patients with advanced cancers. In combination with earlier detection of metastatic spread to the brain, however, these advances have led to progressively increasing prevalence of patients with brain metastasis, which threatens to compromise gains made in systemic therapy. The chemotherapeutic treatment of brain metastases is severely impeded by the presence of the BBB, which minimizes effective access of most cancer drugs to the sites of intracerebral lesions. Consequently, it is essential to find novel approaches to more effectively penetrate, or perhaps entirely circumvent, this significant obstacle.

In this context, we have presented examples of new approaches, derived from the experience with glioblastoma patients, which might become applicable to brain-metastatic patients, as well. Intranasal delivery of POH has yielded encouraging results in patients with primary brain cancer, and it is not unreasonable to rationalize that it should yield similar outcomes in patients with brain metastases. However, while clinical trials with intranasal POH have been initiated for recurrent glioblastoma patients in the United States, no such studies are currently being planned for patients with metastatic brain lesions.

From the large field of drug modifications aimed at the enhancement of BBB penetration, we presented NEO212, where temozolomide, a sub-optimally brain-targeting molecule, was conjugated to POH. Based on in silico prediction, as well as preclinical brain tumor and brain metastasis models, NEO212 appears to be a novel compound with great therapeutic promise. However, the validation of this prediction has to await testing of NEO212 in clinical trials, which have not yet started. Furthermore, based on the success of the intranasal delivery of POH, it might be intriguing to determine whether brain-targeted activity of the conjugated NEO212 compound could be increased even further via intranasal delivery, as well.

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Acknowledgments

The authors would like to thank the members of the Glioma Research Group, an alliance of University of Southern California laboratories dedicated to developing new treatments for tumors of the CNS. Work in the authors’ labs was supported by the Hale Family Research Fund and Sounder Foundation (to Thomas C. Chen) and the California Breast Cancer Research Program (to Axel H. Schönthal).

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Abbreviations

BBB: blood-brain barrier; CNS: central nervous system; CSF: cerebrospinal fluid; IN: intranasal; LMC: leptomeningeal carcinomatosis; NEO212: perillyl alcohol conjugated to temozolomide; PBM: parenchymal brain metastasis; POH: perillyl alcohol; TMZ: temozolomide.

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Author Contributions

All authors contributed to the writing and editing of this manuscript and approved it for submission. The figures were generated by Axel H. Schönthal.

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Conflicts of Interest

The authors declare no conflict of interest.

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Articles from International Journal of Molecular Sciences are provided here courtesy of Multidisciplinary Digital Publishing Institute (MDPI)

We demonstrated that intranasal administration of a p21-Ras lipophilic inhibitor that easily crosses the blood-brain barrier is a safe and non-invasive strategy capable to prolong overall survival of patients with recurrent malignant glioma considered to be at terminal stage.

Long-term Outcome in Patients with Recurrent Malignant Glioma Treated with Perillyl Alcohol Inhalation

  1. THEREZA QUIRICO-SANTOS2⇑

+ Author Affiliations

  1. 1Department of General and Specialized Surgery, Antonio Pedro University Hospital, Fluminense Federal University, Niteroi, RJ, Brazil
  2. 2Department of Cellular and Molecular Biology, Institute of Biology, Fluminense Federal University, Niteroi, RJ, Brazil
  3. 3Department of Neurosurgery, Ipanema Federal Hospital, Ipanema, RJ, Brazil
  4. 4Laboratory for Proteomics and Protein Engineering, Carlos Chagas Institute, Fiocruz/Paraná, Curitiba, PR, Brazil
  5. 5Rio de Janeiro Federal University, Rio de Janeiro, RJ, Brazil
  1. Correspondence to: Thereza Quirico-Santos, Laboratory of Cellular Pathology, Institute of Biology, Fluminense Federal University, Niteroi, RJ, 24020-141, Brazil. Tel: +55 2126292305, Fax: +55 2126292268, e-mail: tquirico@vm.uff.br
 
Next Section

Abstract

Aim: This retrospective study aimed to evaluate the long-term response and toxicity of recurrent malignant glioma patients to inhalation chemotherapy with perillyl alcohol (POH). Patients and Methods: The cohort included 117 men and 81 women with primary glioblastoma multiforme (GBM; n=154), grade III astrocytoma (AA; n=26) and anaplastic oligodendroglioma (AO; n=5). POH inhalation schedule 4-times daily started with 66.7 mg/dose; 266 mg/day and escalated up to 133.4 mg/dose; 533.6 mg/day. Clinical toxicity and overall survival following treatment were compared with tumor size, topography, extent of peritumoral edema and histological classification. Results: Adhesion to the protocol was high (>95%), POH (533.6 mg/daily) occasionally caused nose soreness but rarely nosebleed. Tumor size, peritumoral edema and the oligodendroglial component influenced response to treatment. Conclusion: After 4 years under exclusive POH treatment, 19% of patients still remain in clinical remission. Long-term POH inhalation chemotherapy is a safe and non-invasive strategy efficient for recurrent malignant glioma.

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overall overleving, hersentumoren, temodal, temozomide, Astrocytomen, Glioblastomen, monoterpene perillyl alcohol, complementair, niet-toxisch


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