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Drug sensitivity testing -- Information for Clinicians

Ex vivo drug sensitivity testing is designed to elucidate individual patient response to cytotoxic drugs in the heterogeneous patient population. Twenty-five or more drugs can be tested, including new cytotoxics. We routinely test leukaemias and lymphomas - most experience is with CLL, AML, NHL and similar diseases - using whatever source of live tumour cells is most readily available.

Drug sensitivity tests are carried out at Bath Cancer Research, a charitably funded research group based at the Royal United Hospital in Bath. Research scientist Dr Andrew Bosanquet, who has twenty-five years experience in this field, leads the team.

Drug Sensitivity Testing Methodology
We use the TRAC assay (Tumour Response to Anti-neoplastic Compounds), a recent development of the DiSC assay - a drug sensitivity testing methodology that has been described in detail [1]. Briefly, mononuclear cells are isolated from blood, lymph node, bone marrow, fluids or tumour and cultured with drugs for 4 days. Then cells are cytocentrifuged onto slides, stained, apoptotic cell death is assessed morphologically, and an LC90 calculated. For each drug, a Drug Sensitivity Index (DSI) is determined by ranking the patient's LC90 within all the LC90 results of patients with the same or, in rare malignancies, similar diagnoses. Results are available within 7 days.

Drug Sensitivity Test Results
Your patient’s relative drug sensitivity and resistance for the drugs tested will be charted. Our drug sensitivity results compare well with subsequent patient response [2-5]. They show that patients who are treated with assay-sensitive drugs are 4 to 8 times more likely to achieve a response than those treated with assay-resistant drugs [5]. Results suggest that survival can be improved by treating with drugs that are assay-sensitive [4,6]. Response and survival benefits are being quantified in an international randomised, controlled clinical trial - the LRF CLL4 trial. As of June 2006, results from this trial are being presented (EHA 2006, ASH 2006). [12].

Limitations of the TRAC assay
Incubating drugs and cells together in the lab and observing loss of live cells integrates the effects of many drug resistance mechanisms. However, a cytotoxicity test is obviously limited in that it cannot take into account patient effects on cell survival in vivo such as liver metabolism, enhanced excretion, effect of other medications, etc.

Cytotoxicity of the antibodies alemtuzumab and rituximab is observed but they also induce cell kill by other methods that this test does not detect: it is not known which method of cell kill is most active in vivo. It is also not possible to determine induction of differentiation or inhibition of angiogenesis with this methodology (i.e. we cannot test thalidomide).

For some resistant tumours there are few effective drugs available to test. We are more likely to identify effective drugs for diseases that are generally drug sensitive. However, drug resistance information is valuable when deciding treatment options as it enables avoiding the morbidity of ineffective therapy.

Obtaining a Drug Sensitivity Profile for your Patient

We need LIVE TUMOUR CELLS within 24 hrs (48 hrs max)

So No Freezing, No Formalin, No Friday dispatch

To ensure good results:

  • Send sufficient tumour cells (1 million cells required per drug tested)
  • Get your sample to us quickly, preferably within 24 hours of harvest or phlebotomy. Use the GPO's 'Special Delivery' or ask us about a courier service
  • Send tumour cells appropriately - blood into EDTA, bone marrow into preservative free heparin, ascites "as is", lymph nodes and solid tumours chopped and placed in culture medium e.g. RPMI 1640
  • Fill in the specimen request form and either e-mail or enclose with specimen

    • Inappropriately dispatched specimens are the largest cause of no TRAC assay result -
    a waste of your time, our time and the patient's time.
    Please take care when sending samples.

    Drugs Currently available for testing
    Bleomycin, carboplatin, chlorambucil, cladribine, cyclophosphamide, cytarabine, daunorubicin, dexamethasone, doxorubicin, etoposide, fludarabine, gemcitabine, hydroxycarbamide (mustine), idarubicin, ifosfamide, melphalan, methylprednisolone, mitoxantrone, paclitaxel (taxol), pentostatin, prednisolone, tioguanine (thioguanine), topotecan, vinblastine, vincristine, vinorelbine.

    The testing of other drugs may be possible prior arrangement.

    Advantages of Choosing Therapy knowing a Patient’s Drug Sensitivity Profile

  • Response is four to eight times more likely to be achieved with assay-sensitive drugs
    • [5,12]
  • Morbidity and mortality associated with ineffective drugs can be avoided

  • Drug resistance induced by ineffective treatment is avoided [8]

  • Relative efficacy of two similar regimens is elucidated
  • Rational treatment choices are possible when no clearly defined treatment protocols exist

  • When standard regimens fail, newer or non-standard regimens can be considered

  • A therapeutic index can be obtained when normal cells are also tested [9,10]
  • Financial savings ensue as responding patients need less supportive therapy [6]

  • Expensive new drugs can be avoided in test-resistant patients [3,4]
  • New therapeutic options can be rationally assessed in end-stage patients [11]

    • Charges for Drug Sensitivity Tests
    Specimens for research projects and clinical trials are not charged.

    NEW until further notice

    June 2006. Bath Cancer Research has launched two far simpler, and therefore cheaper, drug sensitivity tests for CLL. These will allow physicians to test the main cytotoxic drugs of interest at diagnosis and also after the patients first regimen:

    TRAC-0 suggested for untreated CLL patients - testing five drugs at just £95.00 (Euros 150.00). Drugs tested fludarabine, cyclophosphamide, mitoxantrone, chlorambucil, methylprednisolone.

    TRAC-1 suggested for CLL patients at first relapse - testing 10 drugs and costing £195.00 (Euros 300.00).

    Click here for further details.

    Apart from any prior agreement, other NHS tests will cost £395.00 + to test the sensitivity to 20+ cytotoxic drugs.

    Private patients and those from North America - please enquire.

    Accreditation
    Bath Cancer Research was inspected in April 2006 by Clinical Pathology Accreditation (CPA), ref. no. 2769. Its status is "Conditional Approval".

    Turnaround time
    Reports are generally available within 7 days of receiving a sample.

    Laboratory details
    Bath Cancer Research, Wolfson Centre, Royal United Hospital, Combe Park, Bath BA1 3NG, UK
    Tel 01225 824 124. Fax 01225 824 114
    Hours: 8.30-5.30 Mon-Thur, 8.30-5.00 Fri. Out of hours by prior arrangement.

    The Director, Dr Andrew Bosanquet PhD MIBiol MRCPath FRSC, is available for scientific advice and interpretation during office hours.

    References

    1. Bosanquet AG, Bell PB. Enhanced ex vivo drug sensitivity testing of chronic lymphocytic leukaemia using refined DiSC assay methodology. Leuk Res 1996; 20: 143-153.
    2. Bosanquet AG. Correlations between therapeutic response of leukaemias and in vitro drug sensitivity assay. The Lancet 1991; 23: 711-714.
    3. Bosanquet AG, Copplestone JA, Johnson SAN, Smith AG, Povey SJ, Gillingham R, Oscier DG. Response to cladribine in previously treated patients with chronic lymphocytic leukaemia identified by ex vivo assessment of drug sensitivity by DiSC assay. Br J Haematol 1999; 106: 474-476.
    4. Bosanquet AG, Johnson SA, Richards SM. Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay. Br J Haematol 1999; 106: 71-77.
    5. Fruehauf JP, Bosanquet AG. In vitro determination of drug response: A discussion of clinical applications. PPO Updates 1993; 7 (December): 1-16.
    6. Mason JM, Drummond MF, Bosanquet AG, Sheldon TA. The DiSC assay: a cost-effective guide to treatment for chronic lymphocytic leukaemia? Int J Tech Assess Health Care 1999; 15: 173-184.
    7. Catovsky D et al. MRC Chronic Lymphocytic Leukaemia Trial 4 Protocol Document 1999. Link
    8. Bosanquet AG, Bell PB. Novel ex vivo analysis of nonclassical, pleiotropic drug resistance and collateral sensitivity induced by therapy provides a rationale for treatment strategies in CLL. Blood 1996; 87: 1962-1971.

    9. Bosanquet AG, Burlton AR, Bell PB. Parameters affecting the ex vivo cytotoxic drug sensitivity of normal human cells. J Exp Ther Oncol 2002; 2: 53-63.
    10. Bosanquet AG, Bell PB. Ex vivo therapeutic index by drug sensitivity assay using fresh human normal and tumour cells. J Exp Ther Oncol 2004; 4: 145-154.
    11. Bosanquet AG, Burlton AR, Bell PB, Harris AL. Ex vivo cytotoxic drug evaluation by DiSC assay to expedite identification of clinical targets: results with 8-chloro-cAMP. Br J Cancer 1997; 76: 511-518.
    12. Bosanquet AG, Raper SL, Durant J, Scadding SM, Richards SM, Catovsky D. Comparison of ex vivo drug sensitivity by TRAC assay and patient response in the UK LRF CLL4 trial. Haematologica / Hematology Journal 2006: 91 (Suppl. 1); 100 (Abstract #267). European Hematology Association, Amsterdam, 2006.

    Abstracts and pdf versions of the full paper can be obtained for some of these publications from Selected Publications

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