ATP-based Tumor Chemosensitivity Assay Research Articles

Two Novel Long Noncoding RNAs - RP11-296E3.2 and LEF1-AS1can - Separately Serve as Diagnostic and Prognostic Bio-Markers of Metastasis in Colorectal Cancer.

BackgroundLate diagnosis and metastasis are leading causes of the high mortality of colorectal cancer (CRC). Long noncoding RNAs (lncRNAs) have been reported to play a critical role in the development and progression of CRC. This study aimed to explore the clinical significance of 2 novel lncRNAs – RP11-296E3.2 and LEF1-AS1 – including their expression pattern, as well as diagnostic and prognostic values, for metastatic CRC patients.Material/MethodslncRNAs expression was examined in tissues (91 cases) and plasma (60 cases) from CRC patients by real-time quantitative PCR (qRT-PCR), and the correlations between its expression and clinicopathological features and diagnosis values in metastasis were analyzed. TCGA datasets were further used to analyze their utility in prediction of overall survival (OS) and disease-free survival (DFS). ATP-based tumor chemosensitivity assay (ATP-TCA) was used to evaluated tumor chemoresistance.ResultsCompared with adjacent normal tissues, RP11-296E3.2 was significantly downregulated while LEF1-AS1 was significantly upregulated in cancer tissues (p=0.0143, p=0.0322, respectively). High levels of RP11-296E3.2 and LEF1-AS1 in tissues and plasma were correlated with tumor metastasis (p=0.0488, p=0.0252 in tissues, p=0.0331, p=0.1862 in plasma, respectively). Further analysis showed that RP11-296E3.2 sensitivity and specificity in diagnosis of CRC metastasis is better than CEA in plasma (0.690 and 0.621, and 0.621 and 0.500, respectively), and the OS of metastatic CRC patients with higher LEF1-AS1 expression levels in tissues was short (log-rank p<0.05).ConclusionsOur findings suggest that RP11-296E3.2 and LEF1-AS1 could separately serve as potential novel diagnosis and prognostic markers for CRC metastasis.

Evaluation of the in vitro Chemosensitivity and Correlation with Clinical Outcomes in Lung Cancer using the ATP-TCA.

Multiple drug resistance (MDR) to chemotherapeutic agents often leads to a failure to respond to chemotherapy. We utilized an in vitro chemosensitivity test to identify sensitive and effective chemotherapeutic drugs and further elucidated the correlation between the in vivo chemosensitivity and clinical outcomes. Here, we evaluated the in vitro chemosensitivity and MDR of 120 lung cancer patients to eight singledrug chemotherapies and of 291 lung cancer patients to seven chemotherapy regimens using an ATP-based tumor chemosensitivity assay (ATP-TCA). Additionally, the chemosensitivity profiles of lung adenocarcinoma patients (284 cases) and lung squamous cell carcinoma patients (90 cases) to these single-drug and chemotherapy regimens were compared. Furthermore, the correlations between the chemosensitivity and clinical outcomes were investigated in 16 stage III squamous cell carcinoma patients. PTX (51.7%), TXT (43.3%), GEM (12.5%), PTX+DDP (62.5%), TXT+L-OHP (54.3%) and VP-16+DDP (16.2%) had the highest in vitro chemosensitivity rates. Approximately 31.7% of patients developed resistance to all eight single-drug chemotherapies, and 25.8% of patients displayed resistance to all seven chemotherapy regimens. In addition, lung squamous cell carcinoma was significantly more sensitive to GEM and MTA+DDP than lung adenocarcinoma (P<0.05). Further analysis showed that patients with higher drug sensitivity tended to have longer disease-free survival (18 months vs. 8.5 months) than patients displaying drug resistance (P<0.05). These results suggest that the implementation of in vitro drug susceptibility testing before chemotherapy can effectively prevent the occurrence of primary drug resistance and inappropriate drug treatment.

Comparative analysis of ATP-based tumor chemosensitivity assay-directed chemotherapy versus physician-decided chemotherapy in platinum-resistant recurrent ovarian cancer*

Abstract Objective The aim of the study was to evaluate the role of ATP-based tumor chemosensitivity assay (ATP-TCA) in patients with platinum-resistant recurrent ovarian cancer (PRROC). Methods A total of 43 patients with PRROC who underwent chemotherapy based on the results of ATP-TCA in the Cancer Hospital, Chinese Academy of Medical Sciences were included in the present study. As controls, we selected another 43 patients with PRROC who were treated at the physician's discretion within the same time period and had the same clinical characteristics as the patients in the ATP-TCA group. Log-rank test and Cox proportional hazards model were adopted for analysis. Results A total of 86 patients were retrospectively analyzed in the present study. Patients were routinely monitored to evaluate the rate of progression-free survival (PFS). The median follow-up time was 13 months. The PFS for the ATP-TCA and control groups was 5 and 3 months, respectively (P = 0.027). Multivariate analysis showed that the type of treatment was an independent prognostic factor for PFS (P = 0.040; HR: 0.623; 95% CI: 0.313-0.973). Subgroup analysis showed that among patients with a treatment-free interval (TFI) of ≥ 3 months (n = 50), those in the ATP-TCA group had longer PFS than those in the control group (7 vs 4 months, P = 0.010). Meanwhile, the median PFS of patients who underwent ≤ 2 prior chemotherapy regimens (PCR, n = 52) in the ATP-TCA and control groups was 6 months and 4 months, respectively (P = 0.025). Conclusion ATP-TCA-directed chemotherapy might improve the PFS in PRROC. In particular, the survival benefit from ATP-TCA is higher in patients with a TFI of ≥ 3 months or treated with ≤ 2 PCR.

Chemosensitivity testing in ovarian cancer – prospects for the future

Individualization of treatment on the basis of in vitro chemosensitivity testing constitutes one of the aims of contemporary oncology Although previous studies report advantages resulting from chemosensitivity laboratory tests, the issue remains an area of interest. The aim of this study was to discuss chemosensitivity assay methods of ovarian cancer cells. ATP-TCA (ATP-based tumor chemosensitivity assay) is the most investigated chemosensitivity test in ovarian cancer with well-documented efficacy Potentially it is possible to use the xCELLigence system to evaluate chemosensitivity of ovarian cancer cells by measuring their colony volume but application of this method remains in the experimental phase. Optimization of ovarian cancer treatment would improve chemotherapy results, thus increasing the overall survival, improving the quality of patient life, decreasing chemotherapy-related toxicity and resulting in economic benefits owing to better drug use.

The effect of tricyclic antidepressants on cutaneous melanoma cell lines and primary cell cultures

The tricyclic antidepressants have previously been shown to exert activity against glioma cells in vitro. Initial studies in cell lines suggested that this might extend to melanoma cells. We have therefore conducted a study in primary cell cultures from metastatic cutaneous melanoma deposits using a well established ATP-based tumour chemosensitivity assay to confirm and extend these findings. Two cell lines and eight primary cell cultures from metastatic melanoma deposits were exposed to three tricyclic drugs, amitriptyline, nortriptyline and clomipramine, at concentrations ranging from 200 to 6.25 µmol/l in the ATP-based tumour chemosensitivity assay. All three drugs showed activity, although nortriptyline was more active than clomipramine or amitriptyline in both cell lines and primary cell cultures, with an IC50 of 9, 27 and 33 µmol/l, respectively. Tricyclic agents show activity against melanoma in vitro. This could be related to the lysosomal effects based on their cationic amphiphilic properties, or effects at the mitochondrial membrane.

The molecular basis of the chemosensitivity of metastatic cutaneous melanoma to chemotherapy

BackgroundChemotherapy benefits relatively few patients with cutaneous melanoma. The assessment of tumour chemosensitivity by the ATP-based tumour chemosensitivity assay (ATP-TCA) has shown strong correlation with outcome in cutaneous melanoma, but...

Molecular basis of chemosensitivity of platinum pre-treated ovarian cancer to chemotherapy

Background:Ovarian cancer shows considerable heterogeneity in its sensitivity to chemotherapy both clinically and in vitro. This study tested the hypothesis that the molecular basis of this difference lies within the known resistance mechanisms inherent to these patients' tumours.Methods:The chemosensitivity of a series of 31 ovarian tumours, all previously treated with platinum-based chemotherapy, was assessed using the ATP-based tumour chemosensitivity assay (ATP-TCA) and correlated with resistance gene expression measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) in a TaqMan Array following extraction of mRNA from formalin-fixed paraffin-embedded tissue. The results were standardised against a housekeeping gene (PBGD), and assessed by multiple linear regression.Results:Predictive multiple linear regression models were derived for four single agents (cisplatin, gemcitabine, topotecan, and treosulfan), and for the combinations of cisplatin+gemcitabine and treosulfan+gemcitabine. Particularly strong correlations were obtained for cisplatin, gemcitabine, topotecan, and treosulfan+gemcitabine. No individual gene expression showed direct correlation with activity in the ATP-TCA. Genes involved in DNA repair and apoptosis were strongly represented, with some drug pumps also involved.Conclusion:The chemosensitivity of ovarian cancer to drugs is related to the expression of genes involved in sensitivity and resistance mechanisms.

Cross-activity analyses of standard chemotherapy regimens for primary breast cancer using the ATP-based tumor chemosensitivity assay: Pharmacoeconomic implications.

e11033 Background: Chemotherapy (Ctx) for primary breast cancer (PBC) now utilizes expensive drugs, thus emerging important pharmacoecomic implications. This study was initiated to analyze the cross-activity of standard Ctx regimens (Ctx-R) in PBC using the ex vivo ATP-based tumor chemosensitivity assay (ATP-TCA). Methods: Eight Ctx-R were studied in a total of 96 native PBCs: epirubicin (EPI); mitoxantrone (MX); paclitaxel (PCT); docetaxel (DCT); CMF, 4-OH-cyclophosphamide (4-HC) + methotrexate (MTX) + 5-fluorouracil (5-FU); EC, EPI+4-HC; ET, EPI+PCT; NT, MX+PCT. Each Ctx-R was tested at a 1.5 log dose range. Using a semi-quantitative score, individual chemosensitivity score was classified as complete, incomplete, or resistance. Eight head-to-head comparisons were made: CMF versus EC, n = 56; CMF versus PCT, n = 49; CMF versus DCT, n = 34; EC versus PCT, n = 51; EC versus DCT, n = 35; EC versus ET, n = 45; ET versus NT, n = 24; PCT versus DCT, n = 34. For every comparison, the assumed cost reduction if using ATP-TCA directed Ctx was calculated for the tested population regarding the current German prices for both Ctx and supportive drugs and the costs for the ATP-TCA. Results: CMF was at least equal to EC in 47 (84%), to PCT in 37 (76%), and to DCT in 29 PBCs (86%). EC was at least equal to PCT in 41 (80%), to DCT in 28 (80%), and to ET in 28 PBCs (62%). NT was at least equal to ET in 47 PBCs (79%), and PCT was at least equal to DCT in 27 PBCs (80%). The calculated potential cost reduction by ATP-TCA directed Ctx ranged between € 457 (PCT vs. DCT) and € 18.847 (CMF vs. DCT) per treatment. Regarding the whole study population, the potential cost reduction ranged between € 2.550 (PCT vs. DCT) and € 611.819 (CMF vs. DCT). Conclusions: These results are in good agreement to clinical studies showing that novel Ctx-R will benefit only a limited proportion of PBC patients. Systematic analyses using biological methods like the ATP-TCA could help to identify individual patients who are likely to benefit from these Ctx-R whereas the remainder could be equally subjected to less toxic or less costly regimens. Depending on the particular comparison made in this study, the use of the ATP-TCA could lead to a considerable cost reduction in Ctx for PBC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration L.a.n.c.e. mbH L.a.n.c.e. mbH

Resistance gene expression determines the in vitro chemosensitivity of non-small cell lung cancer (NSCLC)

BackgroundNSCLC exhibits considerable heterogeneity in its sensitivity to chemotherapy and similar heterogeneity is noted in vitro in a variety of model systems. This study has tested the hypothesis that the molecular basis of the observed in vitro chemosensitivity of NSCLC lies within the known resistance mechanisms inherent to these patients' tumors.MethodsThe chemosensitivity of a series of 49 NSCLC tumors was assessed using the ATP-based tumor chemosensitivity assay (ATP-TCA) and compared with quantitative expression of resistance genes measured by RT-PCR in a Taqman Array™ following extraction of RNA from formalin-fixed paraffin-embedded (FFPE) tissue.ResultsThere was considerable heterogeneity between tumors within the ATP-TCA, and while this showed no direct correlation with individual gene expression, there was strong correlation of multi-gene signatures for many of the single agents and combinations tested. For instance, docetaxel activity showed some dependence on the expression of drug pumps, while cisplatin activity showed some dependence on DNA repair enzyme expression. Activity of both drugs was influenced more strongly still by the expression of anti- and pro-apoptotic genes by the tumor for both docetaxel and cisplatin. The doublet combinations of cisplatin with gemcitabine and cisplatin with docetaxel showed gene expression signatures incorporating resistance mechanisms for both agents.ConclusionGenes predicted to be involved in known mechanisms drug sensitivity and resistance correlate well with in vitro chemosensitivity and may allow the definition of predictive signatures to guide individualized chemotherapy in lung cancer.

Chemosensitivity and chemoresistance testing in ovarian cancer

Sensitivity testing in ovarian cancer to individualize therapy remains an active area of interest and this has been renewed recently by results from several groups. The clinical results of assay-directed therapy are invariably better than would be expected from empirical treatment, but it has proved difficult to get these tests into practice. Several recent studies suggest that cellular individualized tumour response tests, particularly the ATP-based tumour chemosensitivity assay, can improve the chance of response and probably survival for individual patients. Most tumour response tests show excellent correlation with clinical resistance, but vary in their ability to predict sensitivity. Molecular assays of sensitivity and resistance are less developed in ovarian cancer than in breast cancer, but those using multiple gene signatures show considerable promise. Individualized therapy has the ability to guide the use of chemotherapy as well as newer agents. The development of companion diagnostics for drugs used in ovarian cancer has considerable potential for the future and such assays are already proving useful where there is clinical evidence of equivalence between possible treatments.

Activity of mevalonate pathway inhibitors against breast and ovarian cancers in the ATP-based tumour chemosensitivity assay

Previous data suggest that lipophilic statins such as fluvastatin and N-bisphosphonates such as zoledronic acid, both inhibitors of the mevalonate metabolic pathway, have anti-cancer effects in vitro and in patients. We have examined the effect of fluvastatin alone and in combination with zoledronic acid in the ATP-based tumour chemosensitivity assay (ATP-TCA) for effects on breast and ovarian cancer tumour-derived cells. Both zoledronic acid and fluvastatin showed activity in the ATP-TCA against breast and ovarian cancer, though fluvastatin alone was less active, particularly against breast cancer. The combination of zoledronic acid and fluvastatin was more active than either single agent in the ATP-TCA with some synergy against breast and ovarian cancer tumour-derived cells. Sequential drug experiments showed that pre-treatment of ovarian tumour cells with fluvastatin resulted in decreased sensitivity to zoledronic acid. Addition of mevalonate pathway components with zoledronic acid with or without fluvastatin showed little effect, while mevalonate did reduced inhibition due to fluvastatin. These data suggest that the combination of zoledronic acid and fluvastatin may have activity against breast and ovarian cancer based on direct anti-cancer cell effects. A clinical trial to test this is in preparation.

Tumor lysis syndrome associated with chemotherapy in primary retroperitoneal soft tissue sarcoma by ex vivo ATP-based tumor chemo-sensitivity assay (ATP-TCA)

Tumor lysis syndrome (TLS), a result of rapid cell lysis following tumor therapy, is a well recognized complication during the treatment of rapidly growing tumors. TLS rarely occurs in solid tumors. We present a case report of TLS in a patient with primary retroperitoneal soft tissue sarcoma. TLS occurred in the patient after four days' combinational chemotherapy with cisplatin, adriamycin, and dacarbazine. These drugs were selected on the basis of an ex vivo ATP-based tumor sensitivity assay. TLS was properly controlled in the patient with concomitant remission of the sarcoma. Therefore, precautions should be taken to avoid this potentially fatal complication during treatment of solid tumors, especially with tumors highly sensitive to drugs.

Ex vivo chemosensitivity testing and gene expression profiling predict response towards adjuvant gemcitabine treatment in pancreatic cancer

Efficacy of chemotherapy for pancreatic cancer may be improved by tailoring it to individual chemosensitivity profiles. Identification of nonresponders before initiation of treatment may help to avoid side effects. In this study, primary pancreatic cancer cells were isolated from 18 patients undergoing pancreaticoduodenectomy for pancreatic cancer. Eight commonly used pancreatic cancer cell lines were used as controls. Ex vivo chemosensitivity for gemcitabine, 5-fluorouracil, mitomycin-C, cisplatinum, oxaliplatinum, paclitaxel and a combination of gemcitabine with oxaliplatinum or mitomycin-C was determined using a cellular ATP-based tumour chemosensitivity assay (ATP-TCA). Quantitative real-time–polymerase chain reaction was performed to determine RNA expression levels of genes implicated in chemoresistance. Chemosensitivity towards cytotoxic agents was highly variable in primary pancreatic cancer cells and pancreatic cancer cell lines. ATP-TCA results for gemcitabine correlated to the tissue expression of human equilibrative nucleoside transporter-1 (hENT1). Time to relapse in patients with gemcitabine-sensitive tumours was significantly higher than in patients with chemoresistant pancreatic cancers (P=0.01; 71 vs 269 days). Furthermore, time to relapse in gemcitabine-treated patients was related to hENT1 expression (P=0.0067). Thus, chemosensitivity testing using ATP-TCA in pancreatic cancer is feasible and correlated with time to relapse in gemcitabine-treated patients. This suggests that ATP-TCA testing could be used as a decision-making tool in the adjuvant treatment of pancreatic cancer.

A prospective randomized controlled trial of tumour chemosensitivity assay directed chemotherapy versus physician's choice in patients with recurrent platinum-resistant ovarian cancer

The primary aim of this randomized trial was to determine response rate and progression-free survival following chemotherapy in patients with platinum-resistant recurrent ovarian cancer, who had been treated according to an ATP-based tumour chemosensitivity assay in comparison with physician's choice. A total of 180 patients were randomized to assay-directed therapy (n=94) or physician's-choice chemotherapy (n=86). Median follow-up at analysis was 18 months. Response was assessable in 147 patients: 31.5% achieved a partial or complete response in the physician's-choice group compared with 40.5% in the assay-directed group (26 versus 31% by intention-to-treat analysis respectively). Intention-to-treat analysis showed a median progression-free survival of 93 days in the physician's-choice group and 104 days in the assay-directed group (hazard ratio 0.8, 95% confidence interval 0.59-1.10, not significant). No difference was seen in overall survival between the groups, although 12/39 (41%) of patients who crossed over from the physician's-choice arm obtained a response. Increased use of combination therapy was seen in the physician's-choice arm during the study as a result of the observed effects of assay-directed therapy in patients. Patients entering the physician's-choice arm of the study during the first year did significantly worse than those who entered in the subsequent years (hazard ratio 0.44, 95% confidence interval 0.2-0.9, P<0.03). This small randomized clinical trial has documented a trend towards improved response and progression-free survival for assay-directed treatment. Chemosensitivity testing might provide useful information in some patients with ovarian cancer, although a larger trial is required to confirm this. The ATP-based tumour chemosensitivity assay remains an investigational method in this condition.

Effect of culture conditions on the chemosensitivity of ovarian cancer cell lines

The aim of this study was to define the chemosensitivity profile of a series of human ovarian cancer cell lines representing the human primary ovarian tumours under altered culture conditions and to compare the results with those from tumour-derived cells. In this study, we used a standardized ATP-based tumour chemosensitivity assay to measure the activity of cytotoxics in the seven ovarian carcinoma cell lines and ovarian tumour-derived cells. The use of adherence-free polypropylene plates and a serum-free medium slowed down cell proliferation in all cell lines tested, mimicking the slow growth rate of solid tumours in this type of plastic. The seeding density was optimized for each cell line and was in the range of 2000-4000 cells/well. Heterogenous sensitivity to different cytotoxics was observed in the seven ovarian cancer cell lines tested in the ATP-based tumour chemosensitivity assay. The human ovarian carcinoma cell line, OVCA433, was found to be the most resistant cell line and 75% of the drugs showed an Index(SUM) above 300. Our results suggest that the use of appropriate culture conditions i.e. a serum-free culture environment, adherence-free growth and optimum seeding density can induce cell lines to behave more like tumour-derived cells in response to cytotoxic agents. On the basis of the comparison of chemosensitivity profiles of tumour-derived cells and cell lines derived from the corresponding tumour, a panel of cell lines can be selected. Such a panel could be used to screen and develop anticancer drugs.

Pilot studies of the effect of zoledronic acid (Zometa®) on tumor-derived cells ex vivo in the ATP-based tumor chemosensitivity assay

There is debate regarding the direct effect of bisphosphonates against visceral metastases from solid tumors, despite their proven efficacy against the skeletal complications of metastasis. The aim of this study was to determine whether zoledronic acid showed direct activity against five ovarian cell lines and tumor-derived cells, and whether addition of zoledronic acid to cytotoxic agents increased their cytotoxicity. In this study we used a standardized ATP-based tumor chemosensitivity assay (ATP-TCA) to measure the activity of alendronate, clodronate and zoledronic acid in five ovarian carcinoma cell lines and human solid tumors (breast, lung, ovarian, unknown primary carcinoma, and cutaneous and uveal melanoma) (n=34). We also tested the combination of zoledronic acid with paclitaxel and cisplatin in tumor-derived cells. All five cell lines exhibited greater sensitivity to bisphosphonates than the tumor-derived cells and in all five the IC50 for zoledronic acid was less than 4 muM. In the tumor-derived cells, zoledronic acid showed concentration-dependent inhibition with a median IC50 for all tumors tested of 17 muM and evidence of apoptosis (caspase activation). Simultaneous addition of zoledronic acid to cisplatin or paclitaxel showed no major increase in cytotoxicity. We conclude that the activity of bisphosphonates was greater in cell lines than in tumor-derived cells. However, the pattern of activity of bisphosphonates was the same in cell lines and tumor derived cells. This study suggests a direct, or possibly an indirect, effect of zoledronic acid and other nitrogen-containing bisphosphonates against neoplastic cells, but simultaneous addition with cisplatin or paclitaxel does not substantially increase the activity of the cytotoxic agent.

931 POSTER Chemotherapy directed by the ATP-based tumor chemosensitivity assay versus physician's choice in platinum-resistant ovarian carcinoma: a multicenter prospective randomized controlled trial of the TCA ovarian cancer trial group

931 POSTER Chemotherapy directed by the ATP-based tumor chemosensitivity assay versus physician's choice in platinum-resistant ovarian carcinoma: a multicenter prospective randomized controlled trial of the TCA ovarian cancer trial group

A prospective randomized controlled trial of ATP-based tumor chemosensitivity assay (ATP-TCA) directed chemotherapy versus physician’s choice in patients with recurrent platinum-resistant ovarian cancer

5008 Background: Ovarian cancers show considerable heterogeneity in their response to chemotherapy. We sought to establish whether an ATP-based tumour chemosensitivity assay (ATP-TCA) could aid the choice of chemotherapy and improve outcome, based on encouraging results from a previous case control study (Kurbacher et al., Anti-Cancer Drugs 1998; 9: 51–7). Methods: The primary aim of this randomized open label trial was to determine response rate and progression free survival (PFS) following chemotherapy in patients with platinum-resistant recurrent ovarian cancer treated according to the ATP-TCA, or by physician’s choice. All patients showing evidence of progression within 6 months of cessation of primary platinum-based therapy were eligible, if they were fit for further chemotherapy. The study was designed to accrue 180 patient equally between the two arms to detect a 20% difference in outcome with 80% power and 99% confidence. Results: A total of 180 patients were randomised to assay-directed (n = 94) or physician’s choice chemotherapy (n = 86). In each case, tumor or ascitic fluid was sent from the treating centres (n = 10) for assay to one of two central laboratories (UK or Germany). Median follow-up at analysis was 18 months. Treatment choice was balanced between the groups, with increased use of combination therapy in the physician’s choice arm during the study. Response was assessable in 147 patients with 31.5% of patients achieving a partial/complete response in the physician’s choice group, compared with 40.5% in the assay-directed group. ITT analysis showed a median progression-free survival (PFS) of 93 days in the physician’s choice group and 104 days in the assay-directed group (Logrank p < 0.14). There was no difference in overall survival between the groups, and none of the differences observed achieved statistical significance. Conclusions: This study shows a trend towards improved response and PFS for assay-directed treatment with high response rates in both arms, probably due to the balanced use of combination therapy designed using the ATP-TCA in this poor prognosis group of patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CanTech Ltd., LANCE CanTech Ltd., LANCE

Combination chemotherapy in advanced gastrointestinal cancers: ex vivo sensitivity to gemcitabine and mitomycin C.

Advanced or metastatic disease is common in both oesophagogastric and colorectal cancers, with poor 5-year survival despite palliative chemotherapy. We have investigated the sensitivity of gastrointestinal tumours to gemcitabine in combination with mitomycin C (GeM), using a modified ex vivo ATP-based tumour chemosensitivity assay (ATP-TCA). Tumour material from 41 colorectal and 22 oesophagogastric cancers were assessed. The GeM combination showed variable but definite activity in most of the samples tested. The results show that GeM achieves >95% inhibition at concentrations within the range achievable clinically in 60% of colorectal tumours (21 out of 35) and 38% of oesophagogastric tumours (five out of 13) tested. We did not identify any significant difference in sensitivity using concurrent or sequential exposure of tumour-derived cells to these two drugs. The results from this study suggest that GeM may be a useful combination in the treatment of advanced gastrointestinal malignancy.

ATP chemosensitivity testing in ovarian and breast cancer: early clinical trials.

After disappointing results achieved with older chemosensitivity tests such as the human tumor clonogenic assay (HTCA) during the 1980s, the last decade has seen a renaissance of the concept of individualized chemotherapy in oncology, markedly stimulated by the development of newer nonclonogenic assays. These methods appear to be able to overcome major technical limitations associated with older assays, now allowing for successful testing of most of the tumor specimens submitted. Currently, the ATP-based tumor chemosensitivity assay (ATP-TCA) can be regarded as the most sophisticated assay to investigate both solid samples and effusions derived from patients with various organ tumors. During the last 5 years, the ATP-TCA has been used successfully to screen for novel drug combinations for further clinical use in both ovarian and breast cancer such as mitoxantrone plus paclitaxel (NT) and treosulfan plus gemcitabine (TG), respectively. Clinical trials that have been set up in heavily pretreated patients with recurrent ovarian or breast cancer have convincingly confirmed the high activity of these combinations previously demonstrated in preclinical investigations using the ATP-TCA. In a recent phase II trial performed in 59 patients with relapsed ovarian carcinoma, ATP-TCA-directed therapy was able to triple the response rate and to double the survival time, compared with published empirical chemotherapy regimes. Preliminary results with ATP-TCA-directed therapy in breast cancer also evidenced promising response rates. These results have been confirmed by additional prospective clinical trials using other types of modern nonclonogenic assays. A phase III trial that is now actively recruiting patients with platinum-refractory ovarian cancer to verify the promising phase II studies will prove the further value of the ATP-TCA as a predictor applicable in routine clinical oncology.