Drug Resistance Testing

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Update 2007:From ‘European Urology’ – A Chemosensitivity Test for Superficial Bladder Cancer Based on Three-Dimensional Culture of Tumour Spheroids: “Our assay allows determining sensitivity to several drugs in superficial bladder tumours. It might be used in clinical practice to select the best drug for each patient. It also has experimental utility in investigating the effect of new drugs or combinations.” The study also looked at antibiotics VPM(verapamil)and ciprofloxacin (CIPRO) and it was shown that VPM reverted resistance to the commonly used intravesical chemo drug, Epirubicin. CIPRO showed no effect on bladder tumour spheroids.

Juan Pablo Burgués, Luis Gómez, José Luis Pontones, César David Vera, Juan
Fernando Jiménez-Cruz, Mariano Ozonas
Department of Urology, University Hospital Son Dureta, Palma de Mallorca,
Spain; Department of Urology, University Hospital La Fe, Valencia, Spain
Volume 51, Issue 4, Pages 962-970 (April 2007) PUBMED

Update 2005: Japanese researchers report: Predicting Response to Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Neoadjuvant Chemotherapy for Bladder Cancers through Genome-Wide Gene Expression Profiling.

PURPOSE: Neoadjuvant chemotherapy for invasive bladder cancer, involving a regimen of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC), can improve the resectability of larger neoplasms for some patients and offer a better prognosis. However, some suffer severe adverse drug reactions without any effect, and no method yet exists for predicting the response of an individual patient to chemotherapy. Our purpose in this study is to establish a method for predicting response to the M-VAC therapy.EXPERIMENTAL DESIGN: We analyzed gene expression profiles of biopsy materials from 27 invasive bladder cancers using a cDNA microarray consisting of 27,648 genes, after populations of cancer cells had been purified by laser microbeam microdissection.
RESULTS: We identified dozens of genes that were expressed differently between nine “responder” and nine “nonresponder” tumors; from that list we selected the 14 “predictive” genes that showed the most significant differences and devised a numerical prediction scoring system that clearly separated the responder group from the nonresponder group. This system accurately predicted the drug responses of 8 of 9 test cases that were reserved from the original 27 cases. Because real-time reverse transcription-PCR data were highly concordant with the cDNA microarray data for those 14 genes, we developed a quantitative reverse transcription-PCR-based prediction system that could be feasible for routine clinical use.
CONCLUSIONS: Our results suggest that the sensitivity of an invasive bladder cancer to the M-VAC neoadjuvant chemotherapy can be predicted by expression patterns in this set of genes, a step toward achievement of “personalized therapy” for treatment of this disease.

Takata R, Katagiri T, Kanehira M, Tsunoda T, Shuin T, Miki T, Namiki M, Kohri K, Matsushita Y, Fujioka T, Nakamura Y.Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Clin Cancer Res. 2005 Apr 1;11(7):2625-36. PMID: 15814643 [PubMed – in process]


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Read about the new American assay being studied by NCI-backed researchers, COXEN, a chemosensitivity test that can help determine response to commonly used bladder cancer chemotherapy drugs, click here

Cell Culture Drug Resistance Assays are for help in evaluating which chemos would be less likely to have an effect on your own personal cancer cells. For the great majority of people with bladder cancer, the issue of drug resistance testing will not become an issue since 80% of bladder tumors are superficial and intravesical chemotherapy is preferred over systemic in these cases. However, approximately half of those who present with muscle invasive disease upon diagnosis will not survive 5 years in spite of aggressive treatment. For these cases, CCDRT may prove to be a helpful tool.

The medical community generally disdains use of these assays and they are not yet an accepted modality of determining which chemos should be used. The results of years of clinical trials on patient populations are considered enough indication on how an individual will respond. The percentage of patients that must respond to a drug before it is approved varies from as low as 20% to as high as 80%, depending on the type of cancer. Thereafter it is used routinely for all patients with the same form of cancer, though unfortunately a drug that helps one person does not necessarily mean that it will help all people with the same diagnosis.

2007 A change in trend may be dawning, see the interesting (in vivo) study, “Prediction of drug combination chemosensitivity in human bladder cancer PUBMED
The authors state, “The choice of therapy for metastatic cancer is largely empirical because of a lack of chemosensitivity prediction for available combination chemotherapeutic regimens. Here, we identify molecular models of bladder carcinoma chemosensitivity based on gene expression for three widely used chemotherapeutic agents: cisplatin, paclitaxel, and gemcitabine… predictions were prospectively evaluated on a series of 15 randomly chosen bladder carcinoma cell lines. Overall, 80% of the predicted combinations were correct (P = 0.0002). Together, our results suggest that chemosensitivity to drug combinations can be predicted based on molecular models and provide the framework for evaluation of such models in patients undergoing combination chemotherapy for cancer. If validated in vivo, such predictive models have the potential to guide therapeutic choice at the level of an individual’s tumor.”
* Havaleshko DM, * Cho H, * Conaway M, * Owens CR, * Hampton G, * Lee JK, * Theodorescu D. Department of Molecular Physiology and Biological Physics, University of Virginia Health Sciences Center, Box 422, Charlottesville, VA 22908, USA.

Chemosensitivity Testing– by Gregory D. Pawelski

When a patient has an infection, doctors often send a sample of infected blood or tissue to a lab where they can grow the bacteria and see which antibiotics are most effective (called Bacterial Culture and Sensitivity Testing). Chemosensitivity testing is an attempt to do something similar for cancer; fresh samples of the patient’s tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. It is highly desirable to know what drugs are effective against your particular cancer cells before highly-toxic agents are systemically administered to your body.

One approach to individualizing patient therapy is chemosensitivity testing. Chemosensitivity assay is a laboratory test that determines how effective specific chemotherapy agents are against an individual patient’s cancer cells. Often, results are obtained before the patient begins treatment. This kind of testing can assist in individualizing cancer therapy by providing information about the likely response of an individual patient’s tumor to proposed therapy. Chemosensitivity testing may have utility at the time of initial therapy, and in instances of severe drug hypersensitivity, failed therapy, recurrent disease, and metastatic disease, by providing assistance in selecting optimal chemotherapy regimens.

All available chemosensitivity assays are able to report drug “resistance” information. Resistance implies that when a patient’s cancer cells are exposed to a particular chemotherapy agent in the laboratory, the cancer cells will continue to live and grow. Some chemosensitivity assays also are able to report drug “sensitivity” information. Sensitivity implies that when a patient’s cancer cells are treated with a particular chemotherapy agent in the laboratory, that agent will kill the cancer cells or inhibit their proliferation.

The goal of all chemosensitivity tests is to determine the response of a patient’s cancer cells to proposed chemotherapy agents. Knowing which chemotherapy agents the patient’s cancer cells are resistant to is important. Then, these options can be eliminated, thereby avoiding the toxicity of ineffective agents. In addition, some chemosensitivity assays predict tumor cell sensitivity, or which agent would be most effective. Choosing the most effective agent can help patients to avoid the physical, emotional, and financial costs of failed therapy and experience an increased quality of life.

Fresh samples of the patient’s tumor from surgery or a biopsy are grown in test tubes and tested with various drugs. Drugs that are most effective in killing the cultured cells are recommended for treatment. Chemosensitivity testing does have predictive value, especially in predicting what “won’t” work. Patients who have been through several chemotherapy regimens and are running out of options might want to consider chemosensitivity testing. It might help you find the best option or save you from fruitless additional treatment. Today, chemosensitivity testing has progressed to the point where it is 85% – 90% effective.

Chemosensitivity testing might help you find the best option, or save you from fruitless additional treatment. Another situation where chemosensitivity testing might make particularly good sense is in rare cancers where there may not be enough experience or previous ideas of which drugs might be most effective.

Finally, there has been a veritable deluge of new approvals of cytotoxic drugs in recent years as the tortuous FDA process has been speeded and liberalized. In many cases a new drug has been approved on the basis of a single very very narrow indication. But these drugs may have many useful applications – and it’s going to take years to find out. Chemosensitivity testing offers a way of seeing if any of these new drugs might apply to your specific cancer.

Another Name

Cell Culture Drug Resistance Testing refers to laboratory testing of a patient’s own cancer cells with drugs that may be used to treat the patient’s cancer. A group of lab tests known as human tumor assay systems (HTAS) can aid oncologists in deciding which chemotherapies work best in battling an individual patient’s form of cancer. The assay is a lab test performed on a biopsy specimen containing living cancer cells. It’s used to determine the sensitivity or resistance of malignant cells to individual chemotherapy agents. Depending on how well the tumor cells respond to each chemotherapy agent, they are rated as sensitive, resistant or intermediate to chemotherapy. The concept is that you are better off using a chemotherapy drug that your tumor reacts to strongly than one your tumor resists.

There have been over 40 publications in peer-reviewed medical literature showing correlations between cell-death assay test results and the results of clinical chemotherapy in more than 2,000 patients. In every single study, patients treated with drugs active in the assays had a higher response rate than the entire group of patients as a whole. In every single study, patients treated with drugs inactive in the assays had lower response rates than the entire group of patients. In every single study, patients treated with active drugs were much more likely to respond than patients treated with inactive drugs, with assay-active drugs being 7 to 9 times more likely to work than assay-inactive drugs. A large number of peer-review publications also reported that patients treated with assay-tested “active” drugs enjoyed significantly longer survival of cancer than patients with assay-tested “negative” drugs.

Listing of “Reputable” Labs USA:

These labs will provide you and your physician with in depth information and research on the testing they provide.

Analytical Biosystems, Inc., Providence, Rhode Island. Ken Blackman, PhD. Solid Tumors Only. 1-800-262-6520

Anticancer, Inc., San Diego, CA. Robert Hoffman, PhD. Solid Tumors Only. 1-619-654-2555

Impath, Inc., New York, NY. David Kern, MD Solid Tumors and Hematologics. 1-800-447-8881

Oncotech, Inc., Irvine, CA. John Fruehauf, MD. Solid Tumors and Hematologics. 1-714-474-9262 / FAX 1-714-474-8147

Sylvester Cancer Institute, Miami, FL. Bernd-Uwe Sevin, MD. Solid Tumors Only. (especially GYN). 1-305-547-6875

Human Tumor Cloning Laboratory, San Antonio, TX. Daniel D. Von Hoff, MD. Solid Tumors Only. 1-210-677-3827

Oncovation LLC, New York, N.Y. Howard Bruckner, M.D. Solid Tumors Only. 1-212-514-2422

Rational Therapeutics Institute, Long Beach, CA. Robert A. Nagourney, MD Solid Tumors and Hematologics. 1-562-989-6455

DiaTech Oncology, Brentwood, TN. Vladimir D. Kravtsov, MD, PhD Medical Director 1-615-294-9033

Weisenthal Cancer Group, Huntington Beach, CA. Larry M. Weisenthal, MD, PhD. Solid Tumors and Hematologics. 1-714-894-0011 / FAX 1-714-893-3659

Source: Human Tumor Assay Journal

Gregory D. Pawelski