TÜRKÇe biLGİler




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TÜRKÇE BİLGİLER


1. Genel olarak ONKOGRAM

2. Onkogram nedir

3. Bireysel Kemoterapiyi niçin tercih etmelisiniz

4. Klinikteki Faydaları

5. Onkogram ile ilgili yapılmış çalışmalar

6. Onkogram nasıl uygulanır

7. Numunenin hazırlanması ve gönderimi

8. Onkogram Hakkında Akademik Bilgi


Onkogram Nedir?


Onkogram® kısaca, hastadan alınan dokudan kanser hücrelerini izole ettikten sonra bu hücreleri kanser ilaçlarıyla muamele ederek hangi ilacın etkili ve hangisinin etkisiz olduğunu anlamaya yönelik laboratuvar yöntemlerinin genel adıdır. Onkogram® yapmak amacıyla kullanılabilecek birçok yöntem bulunmaktadır. Bu yöntemlerin içinde bazı tümörlerde (örn. over kanseri) klinikle iyi korelasyon göstermiş ve patentlenmiş bir test bulunmaktadır: Bu testin adı, ATP-Tumor Chemosensitivity Assay (ATP-TCA)’dir. ATP TCA, Faz III klinik çalışmalara kadar ulaşabilmiş ve yüksek deteksiyon hassasiyetine sahip olan luminesans teknolojisiyle çalıştığı için kendisinden önceki onkogram® yöntemlerinin dezavantajlarını büyük ölçüde giderebilmiş bir yöntemdir.


Her kanser hastası moleküler düzeyde bir diğerinden farklıdır. Yani tanısı (örneğin, akciğer kanseri) ve hatta histolojik tipi de (örneğin, küçük hücreli akciğer kanseri) aynı olmasına rağmen hastadan hastaya değişebilen özellikler vardır. Hastaya özgü bu karakteristik yapı o kişinin tedaviye olan yanıtını da belirlemektedir. Günümüzde kanser tedavisindeki başarının (birçok yeni kanser ilaçlarının kullanıma girmesine rağmen) çok iyi denebilecek düzeyde artmamasının nedenlerinden biri de bu farklı yanıt olasılığıdır. Çünkü günümüzde kullanılan tedavi protokolleri aynı tanıyı almış her hastada aynen uygulanmaktadır. Böylece “farklı hastalıklara aynı tedaviyi uygulamak gibi” bir durumla karşı karşıya kalınmaktadır. Bu dezavantajı gidermek kısmen mümkündür. Hastadan alınan tümörlü dokudan izole edilen hücrelerin laboratuvar ortamında çeşitli kanser ilaçlarına olan yanıtı test edilebilir ve hücreleri öldürücü etki ölçülebilir. Bu durumda, hangi kanser ilacının o (test edilen) hastada daha etkili ya da hangisinin etkisiz olabileceğini bir ölçüde anlamak mümkündür. Böylece, hastaya özgü olarak kanser ilaçlarının seçimine karar verilebilir. Yani hastalığa değil hastaya özgü tedaviler oluşturulabilir. Bu tedavilerin seçimine olanak tanıyan laboratuvar yönteminin genel adı Onkogram®’dır.


Bireysel Kemoterapiyi Niçin Tercih Etmelisiniz?


Her insan eşsiz bir şekilde birbirinden farklıdır. Bu cümle, sadece dış görünüş için değil, aynı zamanda hücreler, dokular ve (kanser hastalığı durumunda) tümör dokuları için de geçerlidir. Bu sebepten, kansere karşı kemoterapide kullanılan sitostatik ilaçların tamamı tüm hastalarda etkili olmayacaktır. Peki sizin tedavinizde en etkili ilaç hangisidir? Sitostatik ilaçlardan hangisi sizin tümör hücrelerinizi öldürebilir?

Sitostatik ilaçların tümör hücrelerine olan etkisini saptayan ve yüksek ölçüde duyarlı bir yöntem olan onkogram® metodu bu konuda güvenilir bir bilgi sağlamaktadır. Onkologlar, onkogramın yardımıyla sitostatik ilaçların sizin tümör hücreleriniz üzerine etkileri hakkındaki bu “size özgü” bilgiden yola çıkarak sizin için en uygun kemoterapi protokolünü hazırlayabilmektedirler. Daha da önemlisi toksisiteye sebep olabilecek direnç saptanan ilaçları tedavi protokolünden çıkartabilmektedirler.

Onkogram® sonucuna göre etkisiz (dirençli) olduğu rapor edilen ilaçlara hastanın da yanıt vermeme (tedaviye direnç) olasılığı %90-95 gibi çok yüksek bir değerdedir. Böylece, o ilaçların tedavi protokolünden çıkarılabilmesi sağlanabilmektedir. Bu yapıldığı takdirde ise, hastanın o ilacın yaratacağı toksisiteden ve maliyetten korunması mümkün olabilmektedir. Yada istenirse, o ilaçların yerine onkogram® sonucuna göre hassas olduğu saptanan ilaçlar seçilebilmektedir. Onkogram®, henüz klasik tedavi protokolü belirlenmemiş tümörlerin tedavisinde de ilaç seçimine olanak sağlayabilmektedir. Bunun yanında, primeri bilinmeyen tümörlerin tedavisinde de yararlanılabilecek bir metoddur.

Onkogram® İngiltere, Amerika, Hollanda, Almanya, İsveç, Japonya gibi ülkelerde araştırma bazında gittikçe artan bir öneme sahiptir. Ayrıca, bazı merkezlerde rutin hasta tedavisinde de yararlanılmaktadır. Onkogram® ile ilgili uluslararası yayınları diğer bölümde bulabilirsiniz.


Klinikteki Faydaları


Onkogram® sonucuna göre belirlenen ilaçlarla tedavi protokollerinin düzenlenmesi ve hastaya uygulanması gelecekte en azından kemoterapiye hassas tümör çeşitlerinin tedavisinde mümkün görülmektedir. Böylece, klasik (standart) tedaviler gibi başarı şansı hastadan hastaya değişen (bazen de toksik olduğundan ölüme neden olan) tedaviler yerine hastaya spesifik tedavilerin kullanıma girmesi mümkün olabilir. Bunun ise, kemoterapi protokolünü hazırlayacak hekime fayda sağlayacağı açıktır. Onkogram® en azından bazı nüks etmiş tümörlerin (jinekolojik, hematolojik, meme gibi) tedavisinde potansiyel bir değer taşıyabilir.

Hekimin karar verme sürecinde yardım sağlayacak bir parametre olarak klinikte kullanılması durumunda kemoterapötik ilaçların, hastaya özgü olarak yani daha rasyonel olarak seçimi mümkün olabileceğinden daha iyi tedavi yanıtlarına ve daha uzun yaşam sürelerine ulaşılabilir. Bu konuda yayınlar çıkmaya başlamıştır (Cree at al, 2007).

Günümüzde hastalığa değil hastaya özgü tedavi anlayışının yerleşmeye başlaması, bu tip çalışmalara gereksinim duymaktadır. Kaldı ki, bu yöntemlerin bir başka önemli faydası daha vardır: in vitro (ex vivo) olarak dirençli bulunan ilaçları tespit etmek mümkün olacağından, bu ilaçların hastaya verilmemesi önerilebilmektedir. Böylece, bu ilaçların yaratacağı gereksiz yan etkilerden kaçınılması sağlanabilir. Onkogram® ın daha başka faydaları da bulunmaktadır. Bunlar arasında, primeri (kaynağı) bilinmeyen tümörlerde tedavi seçeneği sağlaması, rekürrens (nüks eden) olgularda tedavi seçeneği sağlaması, henüz tedavi protokolü bilinmeyen nadir tümörlerde tedave olanak sağlaması, hastaya uzun dönemde ilaç giderlerinde azalma sağlaması, komplikasyonlu tedavilerde yol gösterici nitelik taşıması bulunmaktadır.


ONKOGRAM ile ilgili yapılmış çalışmalar



Onkogram®, birbirinden farklı çok sayıda hasta örneğinde geniş çapta değerlendirilmiştir. Değerlendirmeler bu metodun, elde edilen tümör hücreleri için etkili olan ilaçları büyük güvenilirlik payı ile önceden belirleyebildiğini ve hekimin tedaviyi (özellikle nüks olgularında) planlamasında yardımcı bir parametre olarak kullanabileceğini kanıtlamaktadır. Pek çok bilimsel yayın –listesi aşağıda görülmektedir- bu bulguları desteklemektedir.

Literature






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Onkogram Nasıl Uygulanır?


Laboratuarda önce tümör dokusundan tümör hücresi süspansiyonu elde edilir. Bu işlem tümör dokusunu bazı enzimlere maruz bırakmak suretiyle gerçekleştirili. Elde edilen süspansiyon, uygun besiyer ortamına transfer edilir ve sonra hücreler çeşitli (hekimin karar vereceği) sitostatik ilaçlarla muamele edilir. Etkili olan ilaçlar, tümör hücrelerini öldürme yada öldürememe yeteneklerine göre etkisiz olan ilaçlardan ayırt edilir. Numune gönderiminden itibaren 7-8 gün içerisinde sonuç alınabilmektedir.


Standart 8 farklı ilaç yada ilaç kombinasyonları 4 x 106 tümör hücresiyle test edilebilmektedir. Onkogram® %90 oranında değerlendirme yüzdesi sağlar. Laboratuvarımızda uygulanan onkogram yöntemi iyi derecede standardize edilmiş, yayınlanmış çok sayıda çalışmanın bulunduğu ATP-TCA yöntemidir. Bu yöntemde teknolojik olarak günümüzün en hassas teknolojilerinden olan lüminesans teknolojisi kullanılmaktadır.


Numunenin Hazırlanması



Solid tümörler!:


Öncelikle mutlaka laboratuvar ile temasa geçilmelidir. Yönlendirmelere göre hareket edilmelidir. İdeal olarak en az 2 g. yaşar durumda tümör dokusu içeren taze biyopsi veya ameliyat esnasında alınan tümör dokusu örneği, olabildiğince aseptik şartlarda hastadan elde edildikten sonra taşıma çantası içerisinde bulunan numune şişesine koyulmalıdır.

Tarafınızdan eksiksiz doldurulmuş olan onkogram istek ve bilgi formu ile numuneyi içeren numune tüpünü taşıma çantasına uygun şekilde yerleştirdikten sonra laboratuvara en kısa sürede ulaşacak şekilde gönderiniz ve ardından aboratuvara numune gönderiminde bulunduğunuzu telefonla mutlaka bildiriniz.


Numune alımı tarihinden önce tarafımızdan size ulaştırılacak olan numune taşıma çantası içerisinde bulunan numune tüpünü numune alım anına kadar mutlaka +4 ºC’de saklayınız ve buz kalıplarını buzlukta dondurunuz.


Örneklerde, aşırı derecede nekroz, yaşayan hücrelerin sınırlı sayıda olması, bakteriyal kontaminasyon, aşırı parçalanmış yada dondurulmuş olması durumunda numuneler kabul edilmeyecektir.


ÖNEMLİ NOT: Hastaların numune alımından önceki 3 hafta içerisinde radyoterapi yada kemoterapi almamış olmaları gerekmektedir.


Onkogram Hakkında Akademik Bilgi



ANTI-CANCER DRUG RESPONSE ASSAY: AN INCREASING TREND IN DESIGNATION OF TAILORED-CHEMOTHERAPY FOR MORE RATIONAL MANAGEMENT OF CANCER PATIENTS


Engin Ulukaya (MD, PhD)

Uludag University Medical School

Bursa, TURKEY


Summary


Drug response assay, in other words tumor chemosensitivity assay, has long been known but technical difficulties regarding the performance of the assay in the past caused a significant drawbacks. However, recent technological achievements (e.g. luminometric measurements) seem to overcome these difficulties. Therefore, individualization of drug treatment via drug response assay may again take its place in oncology clinics. Promising results regarding the ATP-tumor chemosensitivity assay are reported especially in the treatment of recurrent ovarian carcinoma. Athough its widespread use in clinics needs more randomized studies, the trend in using the assay could be expected to develop fast in parallel with the increasing number of chemotherapeutic agents that are coming in to market.



ANTI-CANCER DRUG RESPONSE ASSAY or TUMOR CHEMOSENSITIVITY ASSAY is called ONKOGRAM in Turkish. Although many chemotherapeutic drugs have been introduced for last 40 years, it seems that there is still no satisfactory improvement in the succesful treatment of cancer patients. This is mainly because cancer is a heterogenous disease, which means responses to same anti-cancer drugs can be various from patient to patient even though they all develop the same organ-originated cancer with histologically same phenotype. Because of this fact, it is not likely to expect the same outcome in all the patients who are treated with the same drug(s).


The systemic treatment of malignancies has been based on physicians’ empirical judgement, relying on data obtained from clinical trials. However, even histopathologically identical tumors behave so differently that the response rate of tumors to the chemotherapeutics was, and still is, sometimes greatly varied. These variations may result in failure of the treatment of cancer patients, or even toxicity which leads to the death of the patients. As it is known, chemoresistance is a key feature of success in cancer treatment. In fact, this is one of the nightmare scenarios which may be faced up during treatment of cancer. Therefore, to know the resistance or sensitivity in advance is of immense importance in the success.


The effectiveness of current therapeutic approaches is limited mainly by tumor heterogeneity, as it is known. That is why one of the aims of basic cancer researchers is to predict the response of patients with cancer to chemotherapeutic agents by employing laboratory methods variously called 'tumor chemosensitivity assays', 'drug response assays', or 'drug sensitivity assays'.


The tumor chemosensitivity assay (TCA) can be used as a tool to let oncologists know about which anti-cancer drugs are more likely to work well enough (or not) on their patients. It is believed that the response rate, the progression free survival as well as the overall survival rate of cancer patients could be improved by performing such a test. More benefits are also expected, as stated below. There are a number of tests being used for this aim as briefly explained in the next sections. To perform the test, the cancer tissue removed from patients during routine surgical operation should send to the laboratory in a medium. After that, as many as up to 20, even 30, different drugs are incubated with the cancer cells isolated from the cancer tissue in order to determine their cell-killing potency.


Prediction of response or overall survival is of immense importance in oncology practice. Therefore, there is no doubt that oncologists would like to make these predictions as early as possible. It would not be an overreaction to say that every oncologist has eagerly this wish. Detecting the chemosensitivity and/or chemoresistance of tumor tissue freshly removed from the patient during routine surgical operation to anti-cancer agents in vitro has appeared to be an attractive way of getting this wish come true. TCAs have already been in use in the field of oncological research and these tests should be able to fill the gap in predictive oncology. There is an increasing trend to develop new methods with this aim [1]. A working tumor chemosensitivity assay would be of immense benefit to the pharmaceutical industry, and to oncologists and their patients [2]. These assays could also be used to design new treatment modalities, as has been reported for recurrent ovarian cancer in a very recent paper [3]. The first experiments regarding this issue date back to the early 1950s [4, 5], but little attention was paid until the well-known paper published in the New England Journal of Medicine in 1978 [6]. The attention was taken a bit further in the 1983 report published in the same journal by Von Hoff [7].


The major applications of TCAs include a. assessment of sensitivity and resistance, b. optimization of therapy for efficacy, toxicity and costs, c. designation of therapy for pretreated/relapsed tumors, d. chemotherapy of metastases of unknown primary tumors, e. chemotherapy of rare tumors. In addition to these, there are more benefits, such as a. evaluation of mechanisms for resistance modulation, b. evaluation of drug interactions on cellular level, c. evaluation of new substances, combinations, and principles, d. evaluation of therapeutic index.


In chemosensitivity assays, there are mainly two approaches: using ready-to-use cell lines or preparing up primary cultures. The cell lines have traditionally been used by pharmaceutical companies. Cell lines have some advantages over primary cultures (e.g. shorter assay time, technically less complication, less labor, quicker to perform) [8] but they are often found to be poorly representative of the behaviour of “real” tumor cells [9]. Therefore, using primary culture, instead of commercially available cell lines, are of immense importance in drug evaluation assays. The common feature of these methods (either for cell lines or primary cultures) is basically the employment of cell culture techniques. Both types differ in their processing, and the technique used to measure sensitivity/resistance. All those techniques involve 4 basic steps: 1) isolation of cells; 2) incubation of cells with anticancer agents for certain period of time (2-6 days); 3) assessment of cell viability; and 4) interpretation of the result.


It seems that there is an increasing trend in the utilization of the tumor chemosensitivity assays. In a recent report, a 3-dimensional ex vivo culture technique was stated to be a useful method for drug development and the prediction of in vivo drug efficiency [10]. ATP-TCA is one of the most recent methods for testing tumor response to drugs in addition to chip-based methodologies in which some other parameters of cell survival (e.g. pH) are monitored and measured at the same time. There is an internationally recognized society for the chemosensitivity testing studies and it is called ISCO (The International Society for Chemosensitivity Testing in Oncology). The ATP-TCA is created by particularly Prof. Dr. Ian Cree (Portsmouth, England) and his co-workers who are founders of the ISCO. In ATP-TCA, tumor cells are cultivated in vitro for 6-7 days with titrated concentrations of chemotherapeutic drugs to evaluate tumor sensitivity and resistance. Microwell culture plates and serum-free culture medium which support the selective growth of tumor cells are used to perform the assay. Its serum free property is a unique feature. This is an important issue because medium used for cell culture often provide considerable growth stimulation, either by the addition of serum or artificial supplements. Therefore, it was reported that testing of tumor-derived cells in serum free medium providing less growth support could have a number of advantages in targeting drugs to the most appropriate tumors [9].


Drug inhibition of tumor cell growth is quantified using a luminometer to measure the light emitted when adenosine triphosphate (ATP) from the cultured tumor cells is converted in the D-luciferin-luciferase bioluminescent reaction:


Luciferase (E.C. 1.13.12.7)

ATP + D-Luciferin AMP + 2Pi + Photon


The ATP-TCA seems to show a significant promise in evaluating the anti-cancer potential of chemotherapeutic drugs against cancer cells isolated from many different kinds of solid tumors. More importantly, it has also reached a phase III clinical trial (in recurrent ovarian cancer), of which results might make a great impact on cancer treatment in near future. ATP-TCA has also been evaluated on many other tumor types.


ATP-TCA utilises serum-free medium called CAM (complete assay medium) which promotes the viability of tumor cells while it inhibits the growth of normal/stromal cells. Selective tumor cell growth is also encouraged by the use of polypropylene microplates which do not permit cell adherence. Its ability to select the survival of cancer cells was shown in 124 specimens under the serum-free conditions by Andreotti et al [11]. They tested 39 breast tumors, 78 ovarian tumor or ascites specimens, and 7 other solid tumors. They reported that the mean proportion of malignant cells was 54% (10-95%  22%) before culture, while it increased to 83% (30-100%  14%) after culture, resulting in the mean increase in the percentage of malignant cells before and after culture being 29%.


ATP-TCA results should be regarded as evaluable if three criteria are met [12]: 1. clear evidence of malignant cell involvement of the sample by cytology or histology, 2. MO (no drug control) values greater than 20 000 RLU indicating the presence of enough number of alive cells in culture system, and 3. evidence of a dose relationship. In the analysis of results, percent tumor growth inhibition (TGI) is calculated for each test drug concentrations (TDC). The calculation is performed as formulated below:

TGI=1.0-[(TDC-MI)/(MO-MI)]x100, where MO=mean counts for no inhibition control cultures, MI=mean counts for maximum inhibition control cultures, and TDC=mean counts for replicate test drug cultures [13].


ATP-TCA seems particularly to be useful in ovarian cancer. In the study of Konecny et al [14], they reported a significant correlation between drug sensitivity/resistance and clinical response (p=0.007). In the same study, the assay demonstrated a sensitivity, spesificity, positive predictive value (PPV), and negative predictive value (NPV) of 95, 44, 66, and 89%, respectively. The NPV in this study is especially notable because it gives an appreciable idea of the patients who will show recurrence within 12 months of post-chemotherapy period. Out of 9 patients, 8 were found in vitro resistant on the basis of sensitivity index, according to the assay. In other study, regarding the cisplatin resistance, it was found that the assay had 90% accuracy for cisplatin resistance of ovarian carcinoma [11]. ATP-TCA has also been evaluated in a pilot study of recurrent ovarian cancer in which therapy was selected on the basis of ATP-TCA results by Kurbacher et al [15]. In the study, 25 patients were treated according to the ATP-TCA results while 30 patients were treated emprically. It was shown that therapy guided by ATP-TCA produced a greater benefit with regard to both overall response rate (ORR) and progression-free survival (PFS) in platinum-refractory patients. Kurbacher at all also stated that ATP-TCA could be regarded as the most sophisticated assay to investigate both solid tumor samples and effusions derived from patients with various organ tumors [16]. In another study, prospective studies are needed to be routinely used of ATP-TCA in selecting drug therapy, although it was regarded having a predictive ability for drug response [17].


In addition to this benefit in selecting the best regimen for particular patients, ATP-TCA was also reported that it could succesfully be used for new agent development [9]. Thereby, in the same report, Cree at al suggested that ATP-TCA should limit the number of subsequent phase II/III trials required, saving money and time, while permitting new agents affective for subsets of cancer patients to be introduced faster. There are some conclusions of early clinical trials (oral communication with C. Sartori, Germany) regarding the ATP-TCA in recurrent ovarian cancer that are given below: 1. The ATP-TCA provides promising retrospective ex vivo/in vivo correlations; 2. Both the positive predictive value and the predictive accuracy of the ATP-TCA compares favorably with other predictive assays; 3. A multi-parametric evaluation score including different informations drawn from the dose-response curves appears to be superior to uni-parametric approaches (IC50, IC90, sensitivity index etc.); 4. The ATP-TCA provides a rational approach for preclinical evaluation of novel active combination regimens for ovarian cancer (preclinical phase II studies); 5. Preclinical phase II trials are likely to identify indications for subsequent clinical phase II studies and thus appear to be a time- and cost-saving approach in the development of new chemotherapy protocols; 6. ATP-TCA-directed chemotherapy for recurrent ovarian cancer produces both impressive response rates and promising long-term results (PFS and OAS), as compared to empirical salvage chemotherapy; 7. Responses seen with ATP-TCA-based chemotherapy are often of high quality (CR); very few patients (false positive results) progressed on ATP-TCA-directed chemotherapy; 8. ATP-TCA-directed chemotherapy appears to be of particular value for platinum-refractory patients; the chance to experience long-lasting PFS and OAS is increased to a level normally seen only for platinum-sensitive individuals; 9. Standard platinum-based protocols seem to be not always the best choice for patients with platinum-sensitive disease, whereas patients with refractory tumors may often benefit the most from protocols others than single agent paclitaxel; 10. The ATP-TCA is able to identify patients to benefit from novel regimens which are normally not chosen empirically but accounted for more than 50% of responses seen; 11. Randomized studies are warranted to confirm the promising results of the trials.


In brief, it seems that there are two great benefits to expect from TCAs: Firstly, exclusion of chemotherapeutic agents which are not likely to be effective, thereby avoidance of their potential toxicity. Secondly, selection of chemotherapeutic agents with the greatest likelihood of clinical effectiveness for improved response rates and prolonged survival. In addition to these two great benefit, there are more advantages of using TCA which are briefly mentioned below. 1. Relative efficacy of two similar drug or drug combinations is elucidated; 2. When standard therapy fails, newer or non-standard therapies can be considered; 3. A therapeutic index can be obtained when normal cells are also tested; 4. Financial savings are possible as expensive new drugs can be avoided in test-resistant patients; 5. Sensitivity to radiotherapy can also be measured. TCAs should therefore deserve some attention in order to better management of cancer patients and need to be evaluated in prospective randomised studies. TCA, at least, currently seems to gain a quite respectful position in the treatment decision of recurrent ovarian carcinoma (oral communication with S. Lele, USA).


References


1] Metzger R, Deglmann CJ, Hoerrlein S, Zapf S, Hilfrich J: Towards in-vitro prediction of an in-vivo cytostatic response of human tumor cells with a fast chemosensitivity assay. Toxicology 2001;166:97-108.


2] Cree I, Kurbacher C: Individializing chemotherapy for solid tumors-is there any alternative? Anticancer Drugs 1997;8:541-548.


3] Di Nicolantonio F, Neale MH, Knight LA, Lamont A, Skailes GE, Osborne RJ, Allerton R, Kurbacher CM, Cree IA: Use of an ATP-based chemosensitivity assay to design new combinations of high-concentration doxorubicin with other drugs for recurrent ovarian cancer. Anticancer Drugs 2002;13: 625-630.


4] Wright JL, Cobb JP, Gumport, F. M. Golomb, D. Safadi: Investigation of the relation between clinical and tissue culture response to chemotherapeutic agents of human cancer. N Engl J Med 1957;252:1207-1211.


5] Black MM, Spear FD: Further observations on the effects of cancer chemotherapeutic agents on the in vitro dehydrogenase activity of cancer tissue. J Natl Cancer Inst 1954;14:1147.


6] Salmon SE, Hamburger AW, Soehnlen B, Durie BG, Alberts DS, Moon TE: Quantitation of differential sensitivity of human-tumor stem cells to anticancer drugs. N Engl J Med 1978;298:1321-1327.


7] Von Hoff DD. Send this patient’s tumor for culture and sensitivity. N Engl J Med 1983; 308:154


8] Lu DY, Chen XL, Ding J. Individualized cancer chemotherapy integrating drug sensitivity tests, pathological profile analysis and computational coordination – An effective strategy to improve clinical treatment. Medical Hypotheses 2006;66: 45-51


9] Cree IA, Kurbacher CM: ATP-based tumor chemosensitivity testing: assisting new agent development. Anticancer Drugs 1999;10:431-435


10] Pirnia F, Frese S, Gloor B, Hotz MA, Luethi A, Gugger M, Betticher DC, Borner MM. Ex vivo assessement of chemotherapy-induced apoptosis and associated molecular changes in patient tumor samples. Anticancer Research 2006;26:1765-1772


11] Andreotti PE, Cree IA, Kurbacher CM, Hartmann DM, Linder D, Harel G, Gleiberman I, Caruso PA, Ricks SH, Untch M, Sartori C, Bruckner H: Chemosensitivity testing of human tumors using a microplate adenosine triphosphate luminescence assay: clinical correlation for cisplatin resistance of ovarian carcinoma. Cancer Res 1995;55:5276-5282


12] Cree IA, Kurbacher CM, Untch M, Sutherland LA, Hunter EM, Subedi AMC, James EA, Dewar JA, Preece PE, Andreotti PE and Bruckner HW. Correlation of the clinical response to chemotherapy in breast cancer with ex vivo chemosensitivity. Anticancer drugs 1996;7:630-35


13] Andreotti PE, Linder D, Hartmasnn DM, Cree IA, Pazzaglia M, Bruckner HW. TCA-100 tumor chemosensitivity assay: differences in sensitivity between cultured tumour cell lines and clinical studies. J Biolumin Chemilumin 1994;9:373-78


14] Konecny G, Crohns C, Pegram M, Felber M, Lude S, Kurbacher C, Cree IA, Hepp H, and Untch M. Correlation of drug response with the ATP tumorchemosensitivity assay in primary FIGO stage III ovarian cancer. Gynecologic Oncology 2000;77:258-263


15] Kurbacher CM, Cree IA, Bruckner HW, Brenne U, Kurbacher JA, Muller K, Ackermann T, Gilster TJ, Wilhelm LM, Engel H, Mallmann PK, Andreotti PE. Use of an ex vivo ATP luminescence assay to direct chemotherapy for recurrent ovarian cancer. Anticancer Drugs 1998;9:51-57.


16] Kurbacher CM, Grecu OM, Stier U, Gilster TJ, Janat MM, Untch M, Konecny G, Bruckner HW, Cree IA. ATP chemosensitivity testing in ovarian and breast cancer: early clinical trials. Recent Results Cancer Res 2003;161:221-30


17] O’Meara AT, Sevin B-U. Predictive value of the ATP chemosensitivity assay in epithelial ovarian cancer. Gynecological Oncology 2001;83:334-342

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