Biomedical subjects

Ian A Cree

Publications and source records attributed to Ian A Cree.

31 records · Page 2Linked to original sources

PubMed2003

Outcome of ATP-based tumor chemosensitivity assay directed chemotherapy in heavily pre-treated recurrent ovarian carcinoma.

BACKGROUND: We wished to evaluate the clinical response following ATP-Tumor Chemosensitivity Assay (ATP-TCA) directed salvage chemotherapy in a series of UK patients with advanced ovarian cancer. The results are compared with that of a similar assay used in a different country in terms of evaluability and clinical endpoints. METHODS: From November 1998 to November 2001, 46 patients with pre-treated, advanced ovarian cancer were given a total of 56 courses of chemotherapy based on in-vitro ATP-TCA responses obtained from fresh tumor samples or ascites. Forty-four patients were evaluable for results. Of these, 18 patients had clinically platinum resistant disease (relapse < 6 months after first course of chemotherapy). There was evidence of cisplatin resistance in 31 patients from their first ATP-TCA. Response to treatment was assessed by radiology, clinical assessment and tumor marker level (CA 125). RESULTS: The overall response rate was 59% (33/56) per course of chemotherapy, including 12 complete responses, 21 partial responses, 6 with stable disease, and 15 with progressive disease. Two patients were not evaluable for response having received just one cycle of chemotherapy: if these were excluded the response rate is 61%. Fifteen patients are still alive. Median progression free survival (PFS) was 6.6 months per course of chemotherapy; median overall survival (OAS) for each patient following the start of TCA-directed therapy was 10.4 months (95% confidence interval 7.9-12.8 months). CONCLUSION: The results show similar response rates to previous studies using ATP-TCA directed therapy in recurrent ovarian cancer. The assay shows high evaluability and this study adds weight to the reproducibility of results from different centres.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Chemosensitivity testing as an aid to anti-cancer drug and regimen development.

The ATP-based chemosensitivity assay has proved particularly useful for the evaluation of new anti-cancer agents and combinations. The majority of our publications in this area have concentrated on topoisomerase inhibitors. Comparison of mitoxantrone with doxorubicin convinced us that these two agents were not completely cross-resistant and led to the design of the mitoxantrone + paclitaxel regimen which is now in clinical practice. Re-assessment of treosulfan in uveal melanoma led to the design of a new regimen combining this alkylating agent with gemcitabine, again with rapid introduction of this combination to clinical practice. The assay has recently been used to examine the concentration-activity curve to determine which tumours might benefit from liposomal preparations capable of delivering 4-16 times the standard dose without cardiotoxicity. Assay-directed use of Caelyx is producing encouraging results, and we are now examining this drug in combination with others. We recently showed that XR5000, a combined inhibitor of topoisomerase I and II, was effective against melanoma as well as ovarian cancer, but at concentrations which were unlikely to be achieved in patients. These data confirm our suggestion that use of the assay could reduce the time to introduction of new anti-cancer drugs and the cost of this process.

Adenosine Triphosphate↗

PubMed2003

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.

Adenosine Triphosphate↗

PubMed2003

The chemosensitivity profile of retinoblastoma.

Retinoblastoma is a rare malignant tumour of the developing retina with an incidence of 1 in 20,000 live births in all human races. Chemotherapy is used in retinoblastoma as adjuvant therapy to prevent the growth of metastases and to treat metastatic disease once this has become clinically apparent. Current regimens are based on empirical drug combinations, and few clinical trials have been conducted because of the rarity of this tumour. Chemosensitivity testing offers a way of testing a large number of agents against tumours. The ATP-based chemosensitivity assay (ATP-TCA) has already helped to design new regimens for melanoma and breast and ovarian cancer. Primary retinoblastoma tumour material was obtained from 10 eyes, 7 of which contained sufficient viable cells for ATP-TCA. The results show very high sensitivity to single agents, particularly cisplatin, doxorubicin and vinca aLkaloids. Of the anti-metabolites tested, 5-FU is relatively disappointing (although still active), and gemcitabine shows considerable activity consistent with a cytotoxic effect. The shape of the inhibition curves is interesting. There is a plateau effect with the topoisomerase inhibitors and vinblastine, which is not present with the cisplatin. One tumour was much more resistant than the others tested, particularly to vinblastine but also to the topoisomerase inhibitors, which failed to achieve complete kill at any concentration tested, consistent with a multidrug resistance phenotype. Of the combinations (VAC and VEC), the VAC regimen looks marginally more active in the more resistant of the two cases tested to date. These data confirm that retinoblastoma is a rapidly growing malignancy that is very susceptible to cytotoxic drugs of all types. Chemosensitivity testing provides a practical method of testing new regimens before clinical trials in retinoblastoma patients.

Adenosine Triphosphate↗

PubMed2003

Treosulfan and gemcitabine in metastatic uveal melanoma patients: results of a multicenter feasibility study.

No effective treatment currently exists for metastatic uveal melanoma. However, recent results obtained by an ATP-based tumor chemosensitivity assay have shown consistent activity of treosulfan+gemcitabine in up to 80% of tumor specimens tested. In this study we describe the first clinical results observed with this drug combination at different European centers in patients with metastatic uveal melanoma. Clinical case series of patients with metastatic uveal melanoma were treated with treosulfan+gemcitabine at seven different centers. Fourteen patients, 13 previously untreated and one pretreated with chemoimmunotherapy, were included in the study. Patients received treosulfan+gemcitabine in four different dose regimens. The response rates, progression-free and overall survival, and toxicity were evaluated. The analysis of 14 patients revealed one complete response, three partial responses and a stable disease in eight cases. The objective response rate was 28.6%, the median overall survival was 61 weeks [95% confidence interval (CI) 54-133 weeks], the progression-free survival was 28.5 weeks (95% CI 13-62 weeks) and the 1-year survival rate was 80%. The drugs were well tolerated. The most common side-effects were leuko- and thrombocytopenia. These preliminary results suggest potential therapeutic benefit of treosulfan+gemcitabine treatment in metastatic uveal melanoma and warrant further controlled studies.

Aged↗

PubMed2003

Heterogeneity of chemosensitivity of colorectal adenocarcinoma determined by a modified ex vivo ATP-tumor chemosensitivity assay (ATP-TCA).

Advanced colorectal cancer (CRC) has a poor prognosis with a 5-year survival of only 5% despite treatment with chemotherapeutic agents. Response rate and overall survival varies little between the commonly used single agents, although combinations achieve better outcomes. It is well established that considerable heterogeneity exists between cancers of the same tissue type, but it has been difficult to establish this for CRC. We therefore investigated the heterogeneity of chemosensitivity in CRC using a modified version of the ex vivo ATP-tumor chemosensitivity assay (ATP-TCA) capable of handling infected tumor tissue. Fifty-three specimens of primary solid or malignant effusions of CRC were tested, of which 46 (87%) were evaluable. There were considerable differences in sensitivities between individuals. The most active single cytotoxic agents in the assay were identified as 5-fluorouracil, irinotecan and mitomycin C (MMC). Cells were exposed to combinations of drugs added simultaneously at the same concentrations tested as single agents. All drug combinations achieved greater growth inhibition than drugs used alone. MMC+gemcitabine was found to be the most effective combination in 83% of specimens. The ATP-TCA has previously been shown to be a good predictor of response to chemotherapy in other tissue types. The degree of heterogeneity demonstrated from these results suggests that the ATP-TCA could be used to identify patients who might benefit from specific chemotherapeutic agents alone or in combination.

Adenocarcinoma↗

PubMed2003

Heterogeneity of chemosensitivity of esophageal and gastric carcinoma.

Esophageal and gastric cancer have a poor prognosis, and chemotherapy is rarely of long-term benefit. This may be related in part to heterogeneity of chemosensitivity and to constitutive resistance to individual cytotoxic drugs. This study aimed to demonstrate the degree of heterogeneity of chemosensitivity between tumors. We have examined the heterogeneity of chemosensitivity in esophageal and gastric cancer specimens (n=85) using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). A variety of chemotherapeutic agents were tested. Sixty-four specimens were endoscopic biopsy samples; the remainder were from resection specimens. Cells were obtained from 62 specimens (73%). Eight assays were infected due to contamination/infection of the biopsy material, giving an evaluability rate of 87%. Analysis of the data showed considerable heterogeneity of chemosensitivity. The most active single agents identified by the assay were mitomycin C (56% sensitivity) and 5-fluorouracil (5-FU; 42% sensitivity). Exposure of tumor cells to combinations of drugs showed ECF (epirubicin, cisplatin, 5-FU) and mitomycin C+5-FU to be moderately active regimens. Other experimental drug combinations showed greater activity. There is a marked heterogeneity of chemosensitivity in esophageal and gastric cancers. The degree of heterogeneity observed suggests that the ATP-TCA could be used to individualize chemotherapy by selecting agents for particular patients. This approach provides the rationale for a trial of ATP-TCA-directed therapy to determine whether individualization of chemotherapy might improve patient response and survival.

Adenocarcinoma↗

PubMed2002

Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central vein occlusion.

OBJECTIVE: To establish a role for vascular endothelial growth factor (VEGF) during the onset and clinical course of neovascularization of the iris (NVI) in ischemic central retinal vein occlusion. METHODS: Sixteen patients with ischemic central retinal vein occlusion were followed up for 12 months by clinical examination, retinal and iris angiography, and serial anterior chamber sampling of aqueous humor. Aqueous VEGF level was determined by enzyme-linked immunoassay, and permeability changes were estimated by capillary zone electrophoretic assessment of aqueous albumin. RESULTS: A correlation was found between aqueous VEGF concentrations and the onset, persistence, and regression of NVI; extent of retinal capillary nonperfusion; and vascular permeability. The NVI occurred when aqueous VEGF concentrations were 849 to 1569 pg/mL and regressed fully when they fell below 550 pg/mL. Aqueous concentrations of serum albumin, a marker of increased permeability, correlated with increased VEGF. Placental growth factor was found at low levels only when VEGF levels exceeded 330 pg/mL. The NVI remained VEGF-dependent during the course of the disease, regressing only if VEGF concentrations were reduced after laser ablation of hypoxic retina. CONCLUSIONS: The close temporal correlation between aqueous VEGF levels and the course of neovascularization and permeability in human ischemic central retinal vein occlusion indicates that increased aqueous VEGF level may predict the need for treatment, and that anti-VEGF therapy at an early stage of ischemic central retinal vein occlusion may be therapeutically beneficial.

Adult↗

PubMed2002

Use of an ATP-based chemosensitivity assay to design new combinations of high-concentration doxorubicin with other drugs for recurrent ovarian cancer.

Liposomal doxorubicin (Caelyx/Doxil) has been shown to be active in around 20% of recurrent ovarian cancers. As yet, there is little clinical data on combinations of existing agents with liposomal doxorubicin, despite considerable clinical experience with soluble doxorubicin in combination. In this study, we have used an ATP-based tumor chemosensitivity assay to determine the relative efficacy of high concentrations of doxorubicin tested in combination with cisplatin, treosulfan, 5-fluorouracil (5-FU) or vinorelbine against cells obtained from recurrent ovarian tumor tissue. The results show little enhancement of the efficacy of high concentrations of doxorubicin by 5-FU, cisplatin, or treosulfan. However, vinorelbine+liposomal doxorubicin showed additive inhibition, and this combination is worthy of further testing in clinical trials.

Adenosine Triphosphate↗

PubMed2002

Chemosensitivity of normal human trophoblasts evaluated by a newly developed ATP-based luminescence assay.

Trophoblast injury may be one of the possible causes of fetal distress associated with chemotherapy administered during pregnancy. The purpose of this study was to investigate the ex vivo chemosensitivity of normal trophoblasts (NTB) against commonly used antineoplastic agents. Using the newly developed ex vivo ATP-based trophoblast assay (ATP-TBA), 31 NTB freshly sampled from human placentas (gestational week 7-42) were tested against dactinomycin (Act-D), 5-fluorouracil (5-FU), 4-OOH-cyclophosphamide (4-HC), vincristine (VCR) and methotrexate (MTX) alone or in combination with calcium folate (LV). All agents were studied at concentrations relevant to clinical dosages normally used for chemotherapy of solid neoplasms. Of 31 samples studied with the ATP-TBA, 20 (65%) were evaluable. VCR, Act-D and 4-HC were the most active drugs with 55, 45 and 45% of samples responding ex vivo. Antimetabolites were less active, producing ex vivo response rates of 25 (MTX) and 20% (5-FU), respectively. MTX activity was largely neutralized by adding LV. The chemosensitivity of NTB showed considerable inter-individual variations and did not decrease with increasing gestational age. We therefore conclude that NTB of any gestational age exhibit considerable ex vivo sensitivity against common anticancer agents which is comparable to that observed for various solid tumors. The ATP-TBA may be helpful in planning future trials with both single agents and drug combinations in order to standardize and optimize chemotherapy during pregnancy.

Adenosine Triphosphate↗

PubMed2002

Chemosensitization of solid tumors by modulation of resistance mechanisms.

The number of drugs available for chemotherapy is growing exponentially, and this trend looks set to continue. Chemosensitization strategies use the administration of one drug or agent to render cancer cells more susceptible to a second agent. Modulation of resistance mechanisms due to xenobiotic membrane pumps such as the multidrug resistant proteins, MDR1/P-glycoprotein or MRP is feasible and a number of new agents have been produced to inhibit drug efflux resulting from expression of these molecules. However, tumor cells may express or upregulate more than one such molecule at one time, and this approach is unlikely to benefit every patient. Detoxification mechanisms mediated by glutathione conjugation or metallothionein are also responsible for resistance--the former has been linked to MRP-mediated resistance. Again, modulation is possible but may increase the toxicity of drugs to normal tissues and an increased therapeutic index is not guaranteed. Tumors exposed to DNA damaging agents often upregulate DNA repair mechanisms and this contributes to resistance. Different pathways perform the repair of different forms of DNA damage, and it is difficult to inhibit all of these. Nevertheless, inhibition of DNA repair can re-sensitize tumors to chemotherapy and is increasingly exploited. One of the most successful and widely used approaches is to combine gemcitabine with an alkylating or platinating agent. While gemcitabine may inhibit DNA polymerases directly, this cytidine analog is also likely to be incorporated by DNA repair leading to activity against non-cycling cells, which form the majority of the neoplastic cell population in most solid tumors. Oncologists should take account of potential resistance mechanisms when treating patients: it is often feasible to design combinations with old or new drugs which exploit these apparent weaknesses to the patient's advantage.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Chemosensitization of solid tumor cells by alteration of their susceptibility to apoptosis.

Chemosensitization strategies use the administration of one drug or agent to render cancer cells more susceptible to a second agent. Usually this involves enhanced drug metabolism, improvement of drug uptake or blockage of resistance mechanisms. Alteration of the susceptibility of cancer cells to apoptosis, the process of individual cell death by which many chemotherapeutic drugs act, shows particular promise for therapy in the future, and is the focus of this review. The dependence of cancer cells on non-neoplastic cells to form solid tumors allows anti-angiogenic therapy to be used in conjunction with chemotherapy to increase the therapeutic index. Chemosensitization strategies are set to become increasingly important in cancer therapy, allowing rational design of synergistic drug combinations at an earlier stage in drug development.

Apoptosis↗

PubMed2002

Mutational analysis of selected genes in the TGFbeta, Wnt, pRb, and p53 pathways in primary uveal melanoma.

PURPOSE: It is known that the pRb pathway cell-cycle inhibitor p16(INK4A) plays a significant role in cutaneous melanoma and that alteration of p16(INK4A), which resides within the 9p21-22 locus that also contains p15(INK4B) and p14(ARF), may occur in up to one third of uveal melanomas. The absence of TGFbeta responsiveness noted in cultured uveal melanoma cells also suggests that the TGFbeta pathway plays a role in the formation of this tumor. Therefore, mutational screening was performed in several key genes in tumor-suppressor pathways that are known to be altered in some uveal melanomas. METHODS: Using denaturing high-performance liquid chromatography (DHPLC) analysis and DNA sequencing, a series of 67 uveal melanomas were screened for inactivating mutations in the TGFbeta pathway members Smad4 and TGFbeta receptor type 2 (TGFbetaR2), the downstream cell-cycle inhibitor p15(INK4B), and the cell-cycle inhibitors p14(ARF) and p16(INK4A). p16(INK4A) was also investigated for promoter hypermethylation. Mutational analysis was also performed on the Wnt pathway gene beta-catenin, known to be mutated in approximately one quarter of cutaneous melanoma cell lines. RESULTS: Polymorphisms in p16(INK4A) were detected in 3 of 50 samples, but no inactivating mutations were detected in any of the genes screened. Promoter hypermethylation of p16(INK4A) was detected in 5 of 55 tumors, and loss of heterozygosity of the p16(INK4A) locus was detected in 5 of 16 tumors. CONCLUSIONS: Most primary uveal melanomas do not appear to contain somatic mutations in Smad4, TGFbetaR2, p14(ARF), p15(INK4B), p16(INK4A), or beta-catenin. However, methylation of the p16(INK4A) promoter and loss of heterozygosity of the p14(ARF)-p16(INK4A) locus occurs in some tumors.

Cell Cycle Proteins↗