A randomized, open-label study of the efficacy and safety of AZD4547 monotherapy versus paclitaxel for the treatment of advanced gastric adenocarcinoma with FGFR2 polysomy or gene amplification.

BACKGROUND: Approximately 5%-10% of gastric cancers have a fibroblast growth factor receptor-2 (FGFR2) gene amplification. AZD4547 is a selective FGFR-1, 2, 3 tyrosine kinase inhibitor with potent preclinical activity in FGFR2 amplified gastric adenocarcinoma SNU16 and SGC083 xenograft models. The randomized phase II SHINE study (NCT01457846) investigated whether AZD4547 improves clinical outcome versus paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma displaying FGFR2 polysomy or gene amplification detected by fluorescence in situ hybridization. PATIENTS AND METHODS: Patients were randomized 3:2 (FGFR2 gene amplification) or 1:1 (FGFR2 polysomy) to AZD4547 or paclitaxel. Patients received AZD4547 80 mg twice daily, orally, on a 2 weeks on/1 week off schedule of a 21-day cycle or intravenous paclitaxel 80 mg/m2 administered weekly on days 1, 8, and 15 of a 28-day cycle. The primary end point was progression-free survival (PFS). Safety outcomes were assessed and an exploratory biomarker analysis was undertaken. RESULTS: Of 71 patients randomized (AZD4547 n = 41, paclitaxel n = 30), 67 received study treatment (AZD4547 n = 40, paclitaxel n = 27). Among all randomized patients, median PFS was 1.8 months with AZD4547 and 3.5 months with paclitaxel (one-sided P = 0.9581); median follow-up duration for PFS was 1.77 and 2.12 months, respectively. The incidence of adverse events was similar in both treatment arms. Exploratory biomarker analyses revealed marked intratumor heterogeneity of FGFR2 amplification and poor concordance between amplification/polysomy and FGFR2 mRNA expression. CONCLUSIONS: AZD4547 did not significantly improve PFS versus paclitaxel in gastric cancer FGFR2 amplification/polysomy patients. Considerable intratumor heterogeneity for FGFR2 gene amplification and poor concordance between FGFR2 amplification/polysomy and FGFR2 expression indicates the need for alternative predictive biomarker testing. AZD4547 was generally well tolerated.

Comparison of gemcitabine and carboplatin versus cisplatin and etoposide for patients with poor-prognosis small cell lung cancer.

BACKGROUND: The combination of cisplatin and etoposide (PE) has been a standard treatment for patients with poor-prognosis small cell lung cancer (SCLC). This non-inferiority design trial aimed to determine whether the combination of gemcitabine and carboplatin (GC) results in similar survival but is less toxic with better quality of life. METHODS: Previously untreated patients with SCLC with extensive disease or limited stage with poor prognostic factors were randomly assigned to six 3-weekly cycles of GC or PE. RESULTS: 241 patients (121 GC, 120 PE) were recruited, of which 216 (90%) had died. There was no difference in overall survival (HR 1.01, 95% CI 0.77 to 1.32). Median survival with GC and PE was 8.0 and 8.1 months, respectively. Median progression-free survival was 5.9 months with GC and 6.3 months with PE. Grade 3 or 4 myelosuppressions were more frequent with GC (anaemia: 14% GC vs 2% PE; leucopenia: 32% GC vs 13% PE; thrombocytopenia: 22% GC vs 4% PE), but these were not associated with increased hospital admissions, infections or fatalities. Grade 2-3 alopecia (68% PE vs 17% GC) and nausea (43% PE vs 26% GC) were more frequent with PE. Patients given GC received more chemotherapy as outpatients (89% GC vs 66% PE of treatment cycles). In QoL questionnaires, more patients receiving PE reported being upset by hair loss (p = 0.004) and impaired cognitive functioning (p = 0.04). CONCLUSIONS: GC is as effective as PE in terms of overall survival and progression-free survival and has a toxicity profile more acceptable to patients. TRIAL REGISTRATION NUMBER: ISRCTN 39679215.

Do delays between diagnosis and surgery in resectable oesophageal cancer affect survival? A study based on West Midlands cancer registration data.

This retrospective study investigates if delays between the diagnosis of cancer of the oesophagus and surgical resection influence long-term survival. Data held by the West Midlands Cancer Intelligence Unit on 800 patients who underwent oesophagectomy for a diagnosis of cancer of the oesophagus or oesophagogastric junction between 1995 and 2000 were reviewed. Six hundred and thirty-two patients treated with curative intention and who had not received neo-adjuvant treatment in the form of radio- or chemotherapy were included in the analysis. The time interval between histological diagnosis and surgical resection was stratified into four groups: less than 3, 3-6, 6-9 and more than 9 weeks. The Cox proportional hazard model was used to test for the independent effect of delays. The results showed no difference in long-term survival according to the delay between histological diagnosis and surgical resection. On multivariate analysis adverse prognostic factors were advanced age, incomplete resection and lymph node involvement. Patients with a longer delay had a higher rate of complete tumour resection suggesting that they were more appropriately selected for the surgical treatment approach. In conclusion we have found no evidence that shorter delays from the date of histological diagnosis to surgical resection are beneficial to long-term survival.

Is the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion in lung cancer always attributable to the small cell variety?

The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a well recognised paraneoplastic phenomenon and the vast majority are associated with small cell lung carcinoma. Rarely however, the non-small cell variety can sometimes be responsible and this report describes such an occurrence. Uniquely in this case, after chemotherapy the paraneoplastic SIADH improved in parallel with a tumour response and this has not been reported previously.

Preoperative mitomycin, ifosfamide, and cisplatin followed by esophagectomy in squamous cell carcinoma of the esophagus: pathologic complete response induced by chemotherapy leads to long-term survival.

PURPOSE: Squamous cell carcinoma of the esophagus remains an aggressive disease with a poor prognosis, even after curative-intent surgery. This article analyzes the impact of preoperative chemotherapy with mitomycin, ifosfamide, and cisplatin (MIC) on a cohort of 68 patients. PATIENTS AND METHODS: From 1988 to 1994, 68 patients with potentially operable squamous cell carcinoma of the esophagus were entered onto two phase II trials of neoadjuvant chemotherapy with mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 and received between two and four cycles of treatment at 3-weekly intervals. Two patients were removed from the analysis when they were found to have malignancy other than squamous cell carcinoma of the esophagus. RESULTS: Forty (61%) of 66 patients had a radiologic response to chemotherapy (18 complete responses and 22 partial responses), and 52 (79%) of 66 patients went on to have the primary tumor resected. There were nine pathologic complete responders, seven of whom remain fit and well after at least 60 months of follow-up. The overall median survival was 12.4 months (95% confidence interval, 9.6 to 18.8 months). The complete response and node-negative patients survived significantly longer than those in other categories (log-rank chi2 = 18.8; P <.001): on average 13 months longer than the node-positive or nonresected category (22.0 v 9.4 months). The toxicity of the regimen was low. CONCLUSION: MIC is an easily administered, well-tolerated, and efficacious regimen as neoadjuvant therapy for patients with squamous cell carcinoma of the esophagus. These results warrant further investigation.

Combined results from three phase II trials of neoadjuvant chemotherapy in operable adenocarcinoma of the oesophagus.

Adenocarcinoma of the oesophagus is a systemic disease at presentation in the majority of patients. This article analyses the impact of preoperative chemotherapy on a cohort of 68 patients. From 1990 to 1996, 68 patients with potentially operable adenocarcinoma of the oesophagus were entered into three sequential Phase II trials of neoadjuvant chemotherapy with cisplatin/mitomycin C/ifosfamide, cisplatin/5-fluorouracil (5-FU) and mitomycin C/cisplatin/5-FU. Twenty-four (35%) patients had a radiological (4 complete; 20 partial) response to chemotherapy, and 52 (76%) went on to have the primary tumour resected. There was only one pathological complete responder. The overall median survival was 13 months (95% confidence interval (CI) 9-16). Survival for the 28 N(0) patients was 34 months (95% CI 14-60). The pattern of failure for resected patients was predominantly systemic (16/17). These results indicate that neoadjuvant chemotherapy followed by surgery for adenocarcinoma of the oesophagus achieves excellent local control. The dominance, however, of distant recurrence after surgery underlines the fact that, in the majority of patients, the only hope of improving results in the future is to develop better systemic therapies.

Hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common cancer of men and eleventh most common cancer of women world-wide. However, because almost every individual who develops liver cancer dies of the disease, HCC is the third most common cause of the cancer deaths in men and seventh most common in women. The treatment of choice for hepatocellular carcinoma remains surgical resection or liver transplantation, in carefully selected cases. In patients with hepatocellular carcinoma not amenable to surgical intervention a variety of different therapeutic interventions have been investigated. These include direct ablation of the tumour using agents such as ethanol or acetic acid, transcatheter arterial chemoembolization, or systemic chemotherapy. The evaluation of their efficacy is compromised by the paucity of adequately powered randomised clinical trials. The main challenge facing the research community over the next decade is to prioritise the most promising treatments and take these forward into multicentre controlled trials. Even if these fail to improve results, they will help reduce the variation in clinical practice by eliminating anecdotal treatment.

Pre-clinical and clinical study of QC12, a water-soluble, pro-drug of quercetin.

BACKGROUND: Quercetin is a naturally occurring flavonoid with many biological activities including inhibition of a number of tyrosine kinases. A phase I, dose-escalation trial of quercetin defined the maximum tolerated dose (MTD) as 1700 mg/m2 three weekly, but the vehicle, dimethyl sulphoxide (DMSO) is unsuitable for further clinical development of quercetin. PATIENTS AND METHODS: A water-soluble, pro-drug of quercetin (3'(N-carboxymethyl)carbomyl-3,4',5,7-tetrahydroxyflavone), QC12 has been synthesised. Six cancer patients received 400 mg of QC12 (equivalent to 298 mg of quercetin), orally on day 1 and intravenously (i.v.) in normal saline on day 14. RESULTS: Following oral administration of QC12 we were unable to detect QC12 or quercetin in plasma. After i.v. administration, we detected peak plasma concentrations of QC12 of 108.7 +/- 41.67 microMolar (microM). A two-compartment model with mean t(1/2)alpha of 0.31 +/- 0.27 hours and mean t(1/2)beta of 0.86 +/- 0.78 hours best described the concentration-time curves for QC12. The mean AUC was 44.54 +/- 13.0 microM.hour and mean volume of distribution (Vd) of 10.0 +/- 6.2 litres (l). Quercetin was found in all patients following i.v. infusion of QC12, with peak levels of quercetin 19.9 +/- 11.8 microM. The relative bioavailability of quercetin was estimated to be 20%-25% quercetin released from QC12. CONCLUSIONS: QC12 is not orally bioavailable. This water-soluble pro-drug warrants further clinical investigation; starting with a formal phase I, IV, dose-escalation study.

A phase II study of the 5-lipoxygenase inhibitor, CV6504, in advanced pancreatic cancer: correlation of clinical data with pharmacokinetic and pharmacodynamic endpoints.

PURPOSE: Primary objective was to determine response rate of patients with advanced pancreatic cancer to a novel lipoxygenase and thromboxane A2 synthetase inhibitor (CV6504); secondary objectives included estimation of pharmacokinetics of CV6504, target-enzyme inhibition, safety and tolerance, quality of life and survival. PATIENTS AND METHODS: Thirty-one patients with advanced pancreatic cancer were planned to receive CV6504, 100 mg TDS, orally for three months, at which point CT scans were performed to assess therapeutic response rates. Steady state concentrations of CV6504 and thromboxane B2 (an indirect measure of thromboxane A2 synthetase (TA2S) inhibition) were made. Of the 31 patients entered into the study, 23 were considered fully evaluable for response. RESULTS: The drug was well tolerated with few side effects; no partial or complete responses were seen, but 10 patients had stable disease at 3 months; quality of life was maintained during therapy; mean CV6504 steady state plasma concentrations of 14 +/- 6 ng/ml resulting in 75 +/- 18% inhibition of TA2S were achieved; median-survival time for all patients considered eligible for assessment of efficacy was 36.6 weeks after the initial dose of study medication. The actuarial one-year survival was approximately 25%. CONCLUSION: CV6504 inhibits its target enzyme in vivo, maintains stable disease in 32% of evaluable patients and is well tolerated.

The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar.

The gene encoding the multidrug resistance P-glycoprotein (P-gp) is duplicated in rodent species and the functional basis for this remains unresolved. Despite a high sequence similarity, the mouse P-gp1a and P-gp1b isoforms show distinct patterns of tissue distribution which suggest a specific role of the P-gp1b isoform in steroid transport. In the present study possible biochemical differences between the isoforms were directly investigated at the level of drug interaction. There was no detectable difference in the affinity or binding capacity of the two isoforms towards [3H]vinblastine at equilibrium. Similarly, the rate at which [3H]vinblastine associates with P-gp was indistinguishable between the two isoforms. Some modest differences were observed in the relative abilities of the multidrug-resistant (MDR) reversing agents CP100-356, nicardipine and verapamil to displace equilibrium [3H]vinblastine binding to P-gp1a and P-gp1b. The steroid hormone progesterone displayed a low affinity (Ki = 1.2 +/- 0.2 microM for P-gp1a and 3.5 +/- 0.5 microM for P-gp1b), suggesting an unlikely role as a physiological substrate. Thus the mouse isoforms do not appear to exhibit functional differences at the level of initial substrate interaction with protein.

The acridonecarboxamide GF120918 potently reverses P-glycoprotein-mediated resistance in human sarcoma MES-Dx5 cells.

The doxorubicin-selected, P-glycoprotein (P-gp)-expressing human sarcoma cell line MES-Dx5 showed the following levels of resistance relative to the non-P-gp-expressing parental MES-SA cells in a 72 h exposure to cytotoxic drugs: etoposide twofold, doxorubicin ninefold, vinblastine tenfold, taxotere 19-fold and taxol 94-fold. GF120918 potently reversed resistance completely for all drugs. The EC50s of GF120918 to reverse resistance of MES-Dx5 cells were: etoposide 7+/-2 nM, vinblastine 19+/-3 nM, doxorubicin 21+/-6 nM, taxotere 57+/-14 nM and taxol 91+/-23 nM. MES-Dx5 cells exhibited an accumulation deficit relative to the parental MES-SA cells of 35% for [3H]-vinblastine, 20% for [3H]-taxol and [14C]-doxorubicin. The EC50 of GF120918, to reverse the accumulation deficit in MES-Dx5 cells, ranged from 37 to 64 nM for all three radiolabelled cytotoxics. [3H]-vinblastine bound saturably to membranes from MES-Dx5 cells with a KD of 7.8+/-1.4 nM and a Bmax of 5.2+/-1.6 pmol mg(-1) protein. Binding of [3H]-vinblastine to P-gp in MES-Dx5 membranes was inhibited by GF120918 (K = 5+/-1 nM), verapamil (Ki = 660+/-350 nM) and doxorubicin (Ki = 6940+/-2100 nM). Taxol, an allosteric inhibitor of [3H]-vinblastine binding to P-gp, could only displace 40% of [3H]-vinblastine (Ki = 400+/-140 nM). The novel acridonecarboxamide derivative GF120918 potently overcomes P-gp-mediated multidrug resistance in the human sarcoma cell line MES-Dx5. Detailed analysis revealed that five times higher GF120918 concentrations were needed to reverse drug resistance to taxol in the cytotoxicity assay compared to doxorubicin, vinblastine and etoposide. An explanation for this phenomenon had not been found.

Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life.

PURPOSE: Chemotherapy for non-small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease. PATIENTS AND METHODS: Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m(2), ifosfamide 3 g/m(2), and cisplatin 50 mg/m(2)) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses. RESULTS: Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P =.14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4. 8 months (PC alone) (P =.03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P =.01) and after adjusting for prognostic factors (P =.01). CONCLUSION: MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.

High-performance liquid chromatographic method for sensitive determination of the alkylating agent CB1954 in human plasma.

A high-performance liquid chromatography (HPLC) method is described for the measurement of the weak alkylating agent CB1954 in human plasma. CB1954 can be used as an innocuous prodrug designed for activation by bacterial nitroreductases in strategies of gene-directed enzyme-prodrug therapy, and becomes activated to a potent bifunctional alkylating agent. The HPLC method involves precipitation and solvent extraction and uses Mitomycin C (MMC) as an internal standard, with a retention time for MMC of 5.85 +/- 0.015 min, and for CB1954 of 10.72 +/- 0.063 min. The limit of detection for CB1954 is 2.9 ng/ml, and this compares favourably with systems involving direct analysis of plasma (limit of detection 600 ng/ml, approximately). The method is now being used for pharmacokinetic measurements in plasma samples from cancer patients entering phase I clinical trials of CB1954. Results using serial plasma samples from one patient are presented. The patient was treated intravenously with CB1954 (6 mg/m2), and plasma clearance of the drug showed biphasic kinetics with alpha half-life 14.6 min, and beta half-life 170.5 min.

Comparison based on age of baseline electrocardiographic abnormalities in non-Q-wave myocardial infarction. VANQWISH Trial Research Investigators. Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital.

OBJECTIVE: To compare the incidence of electrocardiographic abnormalities between older (age > or = 70 years) and younger patients presenting with acute non-Q-wave myocardial infarction. DESIGN: Retrospective review of qualifying electrocardiograms in 918 patients enrolled in the multicenter Veterans Affairs Non-Q-Wave Infarction Strategies In-Hospital (VANQWISH) study. SETTING: Seventeen Department of Veterans Affairs medical centers. PARTICIPANTS: A total of 918 patients (224 > or = 70 years old) with acute non-Q-wave myocardial infarction. MEASUREMENTS: Comparison of electrocardiograms in patients aged > or = 70 years and younger patients for presence of left ventriculary hypertrophy, widened QRS complex, ST and T wave abnormalities, rhythm other than sinus, heart rate > or = 80 beats/minute, and location of acute non-Q-wave myocardial infarction. RESULTS: Left ventricular hypertrophy and ST depression > or = 1 mm were significantly more frequent in older than in younger patients. CONCLUSIONS: Older patients presenting with non-Q-wave myocardial infarction have a greater incidence of left ventricular hypertrophy and ST depression on their electrocardiograms than younger patients. Both of these electrocardiographic findings have previously been associated with increased risk of death and recurrent myocardial infarction and may help account for the worse prognosis of non-Q-wave myocardial infarction in older patients.

Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine.

Galactose-targeted delivery of macromolecules and drug conjugates to asialoglycoprotein receptor (ASGPR) positive cells has been widely documented in animals, although targeting in humans has never been demonstrated. In this study we report the pharmacokinetics and imaging determined in the first patient enrolled in a phase I clinical study of the poly[N-(2-hydroxypropyl)methacrylamide] copolymer bearing doxorubicin and galactosamine, known as PK2. Gradient high performance liquid chromatography (HPLC) evaluation of plasma and urine has been combined with 123I-based imaging to show biphasic clearance of the drug from the plasma (half-lives of 78+/-1 and 990+/-15), and approximately 30% delivery of the drug to the hepatic region, as determined by planar whole body imaging at 24 h. This patient has a multifocal hepatoma, and single photon emission computed tomography (SPECT) analysis showed a ratio of tumour tissue to normal liver uptake of approximately 1:3, at 24 h. On the basis of this patient, effective hepatic targeting can be achieved following an intravenous dose of 20 mg/m2 doxorubicin as PK2, however the therapeutic usefulness of this targeted drug has yet to be established.

Novel therapeutic strategies for colorectal cancer.

Advanced colorectal cancer is a significant cause of cancer mortality in industrialized countries. 5-fluorouracil has remained the principal drug used in treating this disease, and although it has tangibly improved patient outcome, further gains can potentially be made. This review focuses on the current development of novel therapeutic agents which have potential in the treatment of colorectal cancer.

Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.

Determination of quercetin in human plasma by HPLC with spectrophotometric or electrochemical detection.

A reversed-phase high-performance liquid chromatographic method for the determination of quercetin in human plasma following intravenous infusion is described. Quercetin in plasma was extracted with methanol-dimethyl sulphoxide (4:1 v/v) and separated on a C18 Hypersil-BDS column with 44% (v/v) methanol in 0.1 M ammonium acetate (pH 5.15) containing 0.27 mM EDTA as the mobile phase. The drug was detected specifically and sensitively at its absorption maximum of 375 nm, or electrochemically, with a detection limit of 80 ng/mL and 2 ng/mL, respectively.

Anti-proliferative activity and mechanism of action of titanocene dichloride.

Development of resistance to cytotoxic agents is a major limitation to their clinical use. Novel compounds are synthesized with a view to develop non-cross-resistant, less toxic and more potent activity. The detection of the anti-tumour properties of the inorganic compound cisplatin stimulated a broad search for other metal-containing complexes. Titanocene dichloride was synthesized on this basis and has shown potent anti-neoplastic activity in experimental animals. We have examined the in vitro activity of titanocene dichloride in two pairs of platinum-sensitive and resistant human ovarian carcinoma cell lines, A2780/2780CP and CH1/CH1cisR, and in mutated p53- and bcl-2-transfected clones of A2780 cells. A time- and concentration-dependent anti-proliferative effect was observed in all cell lines treated with titanocene dichloride. The drug was found to significantly overcome platinum resistance in the 2780CP and the CH1 cisR cell lines and in the bcl-2 and the mutant p53 transfectants of A2780 cells. Titanocene dichloride induced a block in late S/early G2 phase of the cell cycle; however apoptotic cell death occurred from any phase of cycle. Titanium-DNA adducts were detected in A2780 cells treated with titanocene dichloride using atomic absorption spectrometry, suggesting that DNA may be a target for this drug. In agreement with this finding, p53 accumulated rapidly in drug-treated A2780 cells, indicative of a role for titanocene dichloride as a DNA-damaging agent. We have also performed studies to determine whether titanocene dichloride could demonstrate synergy with other cytotoxic agents in vitro. Isobologram analysis of cytotoxicity data obtained suggests that the combination of titanocene dichloride and 5-fluorouracil (5-FU) is synergistic. The potent in vivo anti-tumour activity of this compound, supported by the encouraging results from two phase I clinical trials, suggests that titanocene dichloride could be a promising novel chemotherapeutic agent.

A novel dosage approach for evaluation of SMANCS [poly-(styrene-co-maleyl-half-n-butylate) - neocarzinostatin] in the treatment of primary hepatocellular carcinoma.

We report a Phase I/II clinical trial of poly-(styrene-co-maleyl-half-n-butylate)-neocarzinostatin (SMANCS) for intra-arterial treatment of hepatoma. Early patients received 4 or 8 mg SMANCS dissolved in Lipiodol; later patients were treated according to tumour size and degree of filling achieved. SMANCS/Lipiodol drained rapidly from normal liver but was retained within tumour interstitium. Tumour nodules filled with SMANCS/Lipiodol usually stabilised and often regressed. No UICC criteria-defined responses were achieved, partly due to difficulties of filling several lesions simultaneously. Signs of therapeutic activity suggest a more extensive clinical study is warranted.