Potentiation of the effect of erlotinib by genistein in pancreatic cancer: the role of Akt and nuclear factor-kappaB.

The epidermal growth factor receptor (EGFR) is a target of new therapies in most nonhematologic cancers. EGFR blockade alone may not be sufficient for the control of growth and invasion of human pancreas cancer because of the independent activation of Akt and nuclear factor-kappaB (NF-kappaB). The expression of EGFR, Akt, and NF-kappaB was determined in six human pancreatic cancer cell lines. Selected cells for specific expression were treated with erlotinib, genistein, gemcitabine, or the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. EGFR, phosphorylated EGFR, phosphorylated Akt, and survivin expressions were determined by immunoblotting. Electrophoretic mobility shift assay was used to evaluate the DNA binding activity of NF-kappaB. Genistein significantly increased (P < 0.05) erlotinib-induced growth inhibition and apoptosis in BxPC-3, CAPAN-2, and AsPC-1 cells. In the BxPC-3 cell line, significant down-regulation of EGFR, phosphorylated Akt, NF-kappaB activation, and survivin was observed in the cells treated with the combination compared with the erlotinib-treated cells. In the HPAC and MIAPaCa cell line, no potentiation of the effects of erlotinib by genistein on cell growth or inhibition of the EGFR/Akt/NF-kappaB was observed. Genistein potentiated growth inhibition and apoptosis of the gemcitabine and erlotinib combination in COLO-357 cell line. Genistein potentiates the growth inhibition and apoptosis induced by erlotinib and gemcitabine in certain pancreatic cancer cells. Akt and NF-kappaB inhibition represents one of the mechanisms for the potentiation of erlotinib- and gemcitabine-induced cell death by genistein.

Phase I study of bryostatin 1 and gemcitabine.

PURPOSE: Bryostatin 1 is a macrocyclic lactone with protein kinase C inhibitory activity. Gemcitabine is a nucleotide analogue with a broad spectrum of anticancer activity. Bryostatin 1 enhanced the activity of antitumor agents including gemcitabine in preclinical models. The primary objective of this phase I study was to determine the recommended doses for phase II trials of bryostatin 1 and gemcitabine. EXPERIMENTAL DESIGN: Eligible patients had histologic or cytologic diagnosis of nonhematologic cancer refractory to conventional treatment; life expectancy of >3 months; normal renal, hepatic, and bone marrow function; and a Southwest Oncology Group performance status of 0 to 2. Gemcitabine was administered i.v. over 30 minutes and was followed by bryostatin 1 by i.v. infusion over 24 hours on days 1, 8, and 15 of a 28-day cycle. Bryostatin 1 (microg/m(2)) and gemcitabine (mg/m(2)) doses were escalated as follows: 25/600, 25/800, 25/1,000, 30/1,000, 35/1,000, and 45/1,000, respectively. RESULTS: Thirty-six patients (mean age, 57 years; male/female 15:21) were treated. The median number of treatment cycles per patient was 3 (range, 0-24). Four patients developed dose limiting toxicities: myalgia, 2; myelosuppression, 1; and elevation of serum alanine aminotransferase levels, 1. Ten grade 3 toxicities were observed (anemia, 2; neutropenia, 5; thrombocytopenia, 3). No treatment-related death was seen. The recommended doses for phase II trials for bryostatin 1 and gemcitabine were 35 microg/m(2) and 1,000 mg/m(2), respectively. Two heavily pretreated patients with breast and colon cancer experienced partial responses lasting 22 and 8 months, respectively. Eight patients had stable disease. CONCLUSION: The combination of bryostatin 1 and gemcitabine seemed to be well tolerated with limited grade 3 toxicity. The recommended dose of bryostatin 1 in combination with full doses of gemcitabine was 35 microg/m(2).

Simultaneous targeting of the epidermal growth factor receptor and cyclooxygenase-2 pathways for pancreatic cancer therapy.

The aims of this study were to determine the effects of (a) combining the epidermal growth factor receptor (EGFR) blocker (erlotinib) and the cyclooxygenase-2 inhibitor (celecoxib) on cell growth and apoptosis in human pancreatic cancer cell lines, (b) baseline EGFR expression on the potentiation of erlotinib-induced apoptosis by celecoxib, and (c) the effects of the combination on the expression of the COX-2, EGFR, HER-2/neu, and nuclear factor-kappaB (NF-kappaB). Baseline expression of EGFR was determined by Western blot analysis in five human pancreatic cancer cell lines. BxPC-3, PANC-1, and HPAC had high EGFR and MIAPaCa had low EGFR. Cells were grown in culture and treated with erlotinib (1 and 10 micromol/L), celecoxib (1 and 10 micromol/L), and the combination. Growth inhibition was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and apoptosis was assayed by ELISA. Reverse transcriptase-PCR was used to evaluate COX-2 and EGFR mRNA. EGFR, COX-2, and HER-2/neu expression was determined by Western immunoblotting. Electrophoretic mobility shift assay was used to evaluate NF-kappaB activation. Growth inhibition and apoptosis were significantly (P < 0.05) higher in BxPC-3, HPAC, and PANC-1 cells treated with celecoxib and erlotinib than cells treated with either celecoxib or erlotinib. However, no potentiation in growth inhibition or apoptosis was observed in the MIAPaCa cell line with low expression of the EGFR. Significant down-regulation of COX-2 and EGFR expression was observed in the BxPC-3 and HPAC cells treated with the combination of erlotinib (1 micromol/L) and celecoxib (10 micromol/L) compared with celecoxib- or erlotinib-treated cells. Celecoxib significantly down-regulated HER-2/neu expression in BxPC-3 and HPAC cell lines. Significant inhibition of NF-kappaB activation was observed in BxPC-3 and HPAC cell lines treated with erlotinib and celecoxib. (a) Celecoxib can potentiate erlotinib-induced growth inhibition and apoptosis in pancreatic cell lines, (b) high baseline EGFR expression is a predictor of this potentiation, and (c) the down-regulation of EGFR, COX-2, and HER-2/neu expression and NF-kappaB inactivation contributes to the potentiation of erlotinib by celecoxib.

Cytochrome p450 and glutathione transferase expression in human breast cancer.

PURPOSE: The cytochrome P-450 (CYP) and glutathione S-transferase (GST) enzyme systems may influence the biological effects of carcinogens, including estrogens. As such, these enzymes may predict the developmental risk of breast cancer, as well as be potential targets for chemoprevention. The purpose of this study was to compare the expression of GST-Pi and CYPs 1A1, 2B6, 2E1, and 3A4 in paired samples of normal and malignant breast tissue from patients with breast cancer and women undergoing reduction mammoplasty. EXPERIMENTAL DESIGN: Expression of CYPs 1A1, 2B6, 2E1, 3A4, and GST-Pi was quantified in breast tissue from 33 patients with breast cancer and in 17 women without history of cancer who underwent reduction mammoplasty. The expression of CYP 1A1, 2B6, 2E1, 3A4, and GST-Pi was quantified by immunoblotting. RESULTS: CYP 1A1, 2E1, and 3A4 expression was significantly lower (P < 0.05) in malignant tissue as compared with morphologically normal adjacent tissue. Conversely, GST-Pi expression was marginally lower in the normal tissue (P = 0.08). No significant difference in enzyme expression was seen between the tissue from reduction mammoplasty and normal tissue from breast cancer patients. There was a trend for higher expression of CYP 2B6 and GST-Pi in the estrogen receptor expressing tumors than those tumors without expression (P > 0.28). CONCLUSION: The expression of these enzymes was similar in morphologically normal breast tissue from patients with or without breast cancer. The expression of CYPs was down-regulated in the tumor tissue. The clinical significance of CYP alterations in breast cancer will need further characterization.

Cytochrome p450 and glutathione transferase expression in squamous cell cancer.

PURPOSE: The cytochrome P-450 (CYP) and glutathione S-transferase (GST) enzyme systems modulate the carcinogenic effects of tobacco. Therefore, the expression of these enzymes may be in part responsible for the observed interindividual and inter-racial differences in the risk of development of squamous cell carcinoma of the head and neck (SCCHN). The first aim of this study was to evaluate the feasibility of measuring the expression of the CYP and GST in target tissue from the head and neck. The second aim was to compare the expression of CYPs 1A1, 2E1, and 3A4 in squamous epithelium from African-American and Caucasian pediatric patients. The third aim was to compare the expression of CYPs 1A1, 2E1, 3A4, and GST-pi on the p16 expression in patients with SCCHN. EXPERIMENTAL DESIGN: The expression of CYP 1A1, 2E1, 3A4, GST-pi, and p16 was quantified by immunoblotting. Expression of CYPs 1A1, 2E1, and 3A4 was quantified in tissue from 160 pediatric patients undergoing tonsillectomy. Expression of CYPs 1A1, 2E1, 3A4, GST-pi, and p16 was determined in 46 resected SCCHN patients. RESULTS: Large interindividual variability in the expression of these enzymes was observed in the pediatric and adult populations. No significant difference was observed in CYP 1A1, 2E1, and 3A4 expression of Caucasian and African-American patients. There was no correlation between p16 and enzyme expression in patients with SCCHN. CONCLUSION: Evaluation of CYP expression in the target tissue of interest is feasible. The clinical significance of CYPs and GST-pi alterations in the risk of developing SCCHN will need to be investigated in larger trials.

Cyclooxygenase-2-dependent and -independent effects of celecoxib in pancreatic cancer cell lines.

Cyclooxygenase-2 (COX-2) is involved in inhibition of apoptosis, potentiation of cell growth, and angiogenesis and as such is a target for drug development. The COX-2 enzyme is frequently overexpressed in pancreatic cancer. The aim of this study was to determine the effects of celecoxib on the growth inhibition and induction of apoptosis by gemcitabine in pancreatic cancer cell lines. Baseline expression of COX-2 enzyme was determined by Western blot analysis in five human pancreatic cancer cell lines. Cells were treated with gemcitabine (100 nmol/L), celecoxib (1, 10, and 50 micromol/L), and the combination. No potentiation in growth inhibition was observed in MIAPaCa cells (low COX-2 expression). However, growth inhibition and apoptosis were significantly increased with celecoxib in the BxPC-3 cells that have a high COX-2 expression. Significant down-regulation of nuclear factor-kappaB activation was observed in BxPC-3 cells treated with celecoxib and gemcitabine. Moreover, down-regulation of COX-2 mRNA and protein expression was also observed in the BxPC-3 cells treated with the combination as compared with the untreated and the celecoxib-treated and gemcitabine-treated cell lines. We conclude that celecoxib potentiates gemcitabine-induced growth inhibition and apoptosis in pancreatic cell lines. In addition to inhibition of the COX-2 enzyme, the celecoxib and gemcitabine combination down-regulated nuclear factor-kappaB activation, which in turn may have contributed to the induction of apoptosis and the down-regulation of transcription of the COX-2 enzyme.

Intensity-modulated radiotherapy (IMRT) and concurrent capecitabine for pancreatic cancer.

PURPOSE: Local failure continues to be a major problem in the management of pancreatic cancer. Delivery of adequate radiation doses to the pancreas is limited by radiation-sensitive normal structures in the upper abdomen. To overcome some of these restrictions, we have developed a regimen of intensity-modulated radiotherapy (IMRT) with concurrent capecitabine. METHODS AND MATERIAL: This is a retrospective analysis of the first 15 patients with adenocarcinoma of the pancreas treated on this regimen (7 as adjuvant therapy after curative resection and 8 patients for unresectable disease). Intensity-modulated radiotherapy was planned using the CORVUS system and delivered with a segmented multileaf collimator, using a 6-MV photon beam and 10 intensity steps. Two target volumes were entered: target 1 consisted of the gross tumor volume (in unresectable cases) or the tumor bed (in postsurgical cases); and target 2 consisted of the draining lymph nodes. Both targets were treated simultaneously in 25 daily fractions, 5 days a week. In the postoperative setting, the total dose to target 1 was 45-54 Gy (median, 54 Gy). For unresectable disease the dose was 54-55 Gy (median, 54 Gy). The total dose to target 2 was 45 Gy in all patients. Patients were treated with one of two six-field beam arrangements found to produce superior dose distributions. Capecitabine was given at 1,600 mg/m(2)/day in two divided doses, 5 days per week, concurrently with radiotherapy. In addition, most patients (73%) received gemcitabine-based chemotherapy. Systemic chemotherapy was given before, after, or both before and after chemoradiotherapy in 47%, 7%, and 20% of patients, respectively. Patients were evaluated on a weekly basis. RESULTS: Treatment was tolerated well. Grade 1/2 nausea/vomiting developed in 8 patients (53%) and Grade 1/2 hematologic toxicity developed in 9 patients (60%). Only 1 patient (7%) had Grade 3 toxicity, a gastric ulceration that responded to medical management. Nine patients (60%) had weight loss (median, 7 lbs; range, 3-12 lbs). The median follow-up time is 8.5 months (10.1 months in patients who are alive). In the resectable group there have been no deaths, and there has been 1 local relapse (14%). In the unresectable group there have been 2 deaths, and the 1-year actuarial survival rate is 69%. Two patients converted to resectability, 5 patients (62.5%) have persistent locoregional disease after chemoradiotherapy, and 1 patient (12%) is locally controlled without surgery. CONCLUSIONS: This regimen of IMRT with tumor-selective radiosensitization is well tolerated. The low toxicity profile compares favorably with that of protocols based on continuous-infusion 5-fluorouracil or gemcitabine, and the preliminary indications of efficacy are encouraging.

Ciprofloxacin inhibits cell growth and synergises the effect of etoposide in hormone resistant prostate cancer cells.

Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer related deaths in men in the United States. Ciprofloxacin is a relatively non-toxic antibiotic that can be easily administered orally with large volume of distribution and good tissue penetration. Studies from others and our laboratory have recently reported its anti-tumor activity in a variety of human tumor cells. In our current experiment, we studied the effect of ciprofloxacin on a hormone resistant prostate cancer (HRPC) cell line, PC-3. Our study shows significant in vitro cell growth inhibition of PC-3 cell line (p=0.0001) and also shows that there is a synergistic increase in the antiproliferative effect of etoposide when these cells are pretreated with ciprofloxacin for 24 h, prior to etoposide exposure (p=0.0001). Western blot analysis of the protein extracts from these cells showed down-regulation of Bcl-2, altering the ratio of Bax:Bcl-2 favoring apoptosis. In our study no significant effect was seen on p21WAF1 expression by the combination of ciprofloxacin and etoposide but there was down-regulation of p21WAF1 gene by ciprofloxacin alone. Ciprofloxacin also inhibited NF-kappaB binding to DNA. Further studies in this area are warranted as the roles of p21WAF1, Bax/Bcl-2 and NF-kappaB may be important molecular events in mediating the antiproliferative and apoptosis inducing effect of etoposide in combination with ciprofloxacin in HRPC cells.

Hormonal therapy for prostate cancer: past, present and future.

Prostate cancer is the second leading cause of cancer mortality in men in the USA. For the past six decades, hormonal therapy has been the main treatment of advanced prostate cancer. Hormonal therapy has developed from a surgical procedure to a complex pharmacological treatment. Trials comparing the efficacy of different monotherapies have demonstrated the equivalence of DES, LHRH agonists and orchiectomy. Combined androgen blockade has been compared with monotherapy. However, the results of the different trials have been conflicting. Novel hormonal therapy schedules involving intermittent treatment and peripheral androgen blockade are currently in clinical trials. The role of hormonal therapy in locally advanced disease as part of a multimodality therapy is a new and rapidly developing aspect of hormonal therapy. The mechanism of hormone refractoriness in prostate cancer is an active area of basic science and translational research.

Systemic therapy for advanced pancreatic cancer.

Death from pancreatic cancer remains high with few long-term survivors. Systemic chemotherapy with 5-fluorouracil-based combinations had minimal impact on natural history of this disease. Several new agents with activity against pancreatic cancer have been identified over the past decade. Gemcitabine has modest activity in this disease. Combination chemotherapy trials incorporating gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, docetaxel or irinotecan show improved outcomes in objective response rates and survival that need to be confirmed in prospectively randomized studies. Advancement in the understanding of the biology of pancreatic cancer has helped identify several molecular targets for the development of novel therapies. Ongoing and future treatment regimens for pancreatic cancer will incorporate traditional cytotoxic drugs and novel targeted therapies.

A review of systemic therapy for advanced pancreatic cancer.

Pancreatic cancer remains an important cause of cancer mortality with few long-term survivors. Improvement in the systemic therapy of pancreatic cancer is necessary to treat the frequently encountered metastatic disease. Several new chemotherapeutic agents with modest activity against pancreatic cancer have been identified over the past decade. Gemcitabine is currently the standard treatment for advanced pancreatic cancer. Combination chemotherapy trials incorporating gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, or irinotecan generally show improved outcomes in objective response rates but with little or no improvement in survival in phase III trials. Novel therapeutic strategies targeting dysregulated molecular pathways in pancreatic cancer cells are currently being explored. Future treatment regimens for pancreatic cancer will probably incorporate conventional cytotoxic drugs and novel targeted agents.

A phase I study of gemcitabine and uracil-ftorfar (UFT)/leucovorin.

BACKGROUND: Gemcitabine and uracil-ftorfar (UFT) are nucleotide analogs with overlapping clinical activity and complementary mechanisms of action. The primary objective of this study was to determine the maximum tolerated dose of UFT/leucovorin and gemcitabine. METHODS: The major eligibility criteria included a diagnosis of nonhematologic cancer with no conventional effective therapy, normal organ function, and Eastern Cooperative Oncology Group performance status of 0-2. The starting doses were 600 mg/m2 gemcitabine weekly for 3 of 4 weeks and 150 mg/m2 UFT daily and 30 mg leucovorin 3 times a day, both for 21 days. Cycles were repeated every 28 days. RESULTS: Twenty-eight patients (male:female 13:15) were treated. The median number of cycles per patient was 3 (range, 0-17). Two of 3 patients on dose level 4 (250 mg/m2 UFT, 800 mg/m2 gemcitabine) developed dose-limiting toxicities consisting of hand-foot syndrome and infection. CONCLUSIONS: The recommended doses for phase II trials are 800 mg/m2 gemcitabine days 1, 8, and 15 and 200 mg/m2 UFT per day and 90 mg leucovorin per day on days 1 through 21.

A phase II study of preoperative capecitabine and radiation therapy in patients with rectal cancer.

OBJECTIVES: The purpose of this study was to evaluate the safety and efficacy of preoperative capecitabine and radiation therapy (RT) in patients with locally advanced rectal cancer (LARC). METHODS: Patients with adenocarcinoma of the rectum stage >or=T3 or >or=N1 were treated with capecitabine 1330 mg/m per day in 2 divided doses days 1 to 42 and 50.4 Gy of RT in 28 1.8-Gy fractions. Patients with metastatic disease were eligible provided that operative intervention on primary site was anticipated. Surgery resection occurred 4 to 6 weeks after completion of preoperative therapy. RESULTS: Thirty eligible patients were enrolled at two institutions. Median age and performance status were 62 years and 90%, respectively. Twenty-eight patients (93%) completed combined modality therapy and 27 underwent resection, including 17 abdominal-perineal and 9 low anterior resections. Three of 27 (11%) had pathologic complete response (pCR) with an additional 7 (26%) having minimal residual disease. Two patients who were felt to require abdominal perineal resection prior to combined modality therapy (CMT) were able to have sphincter-sparing surgery. No patients had progression during CMT which precluded surgical resection. Treatment was well tolerated with >or=grade 3 toxicities limited to diarrhea (5 patients), hand-foot syndrome (1 patient), dermatitis (1 patient). Twenty-four patients are living, 18 with no evidence of disease. CONCLUSIONS: The combination of preoperative capecitabine and RT in patients with LARC has significant antitumor activity, efficacy, and a low toxicity profile.

A phase I study of flavopiridol and docetaxel.

BACKGROUND: Flavopiridol is a cyclin dependent kinase inhibitor. Preclinical models suggest a sequence dependent synergy between flavopiridol and taxanes. The primary objective of this study was to determine the maximum tolerated dose (MTD) of flavopiridol and docetaxel and the influence of flavopiridol on the pharmacokinetics of docetaxel. METHODS: The major eligibility criteria included: a diagnosis of non-hematologic cancer with no conventional effective therapy, normal organ function, and ECOG performance status of 0-2. Patients were treated with docetaxel followed 24 h later by flavopiridol given via continuous intravenous infusion over a 24-h period. The starting doses of docetaxel and flavopiridol were 60 and 60 mg/m2, respectively. Cycles were repeated every 21 days. All patients received diarrhea prophylaxis consisting of bismuth subsalicylate. RESULTS: Ten patients (M:F 4:6; median age 56 years) were treated. The median number of cycles per patient was 2 (range 1-6). Two of the three patients on dose level 1 developed dose-limiting toxicities consisting of neutropenia and fever. Seven patients were subsequently enrolled on dose level -1 (docetaxel 60 mg/m2, flavopiridol 50 mg/m2). One episode of grade 3 diarrhea was reported at dose level -1. CONCLUSIONS: Neutropenia complicated by infection was the major dose-limiting toxicity. The recommended doses of flavopiridol and docetaxel for phase II trials are 50 and 60 mg/m2 every three weeks, respectively.

Sequence dependent potentiation of gemcitabine by flavopiridol in human breast cancer cells.

PURPOSE: Flavopiridol is a novel cyclin dependent kinase (cdk) inhibitor currently in Phase I and II clinical trials. We investigated the interaction between flavopiridol and gemcitabine in two human breast cancer cell lines. Experimental design. MCF-7 [Estrogen receptor (ER) positive] and MDA-MB-231 cells (ER negative) were treated with sub-cytotoxic concentrations of gemcitabine (G), flavopiridol (F), and flavopiridol followed by gemcitabine (F-G), or gemcitabine followed by flavopiridol (G-F) and assayed for biological activity. RESULTS: Growth inhibition assessed by serial cell counting and MTT assay was highest in the G-F group. Significant increase in apoptosis assessed by flow cytometry, poly-ADP-ribose polymerase (PARP) and Caspase-3 degradation was also highest in the G-F group. Expression of pro-apoptotic Bax was up-regulated and anti-apoptotic Bcl-2 was down-regulated in only the G-F treated cells. Significant up regulation of p21(WAF-1) was demonstrated in the G-F group but not in the reverse regimen treated cells. No effect on protein kinase C (PKC) expression was seen in any of the treated cells. CONCLUSIONS: In conclusion, similar to the results in the gastrointestinal cell lines, a sequence dependent potentiation of the effect of gemcitabine by flavopiridol was demonstrated in breast cancer cell lines and it was independent of ER status. This was accompanied by enhanced apoptosis and the up regulation of p21(WAF-1) protein. These results provide rationale for pre-clinical evaluation of this treatment strategy using animal models and in the design of clinical trials of this drug in combination with cytotoxic therapy.

Phase I study of liposomal doxorubicin (Doxil) and cyclophosphamide in solid tumors.

INTRODUCTION: The purpose of this study was to determine the recommended phase II dose (RPTD) of the combination of cyclophosphamide and liposomal doxorubicin (Doxil). PATIENTS AND METHODS: Eligibility criteria included: a diagnosis of non-hematologic cancer with no conventional effective therapy, normal renal, liver and bone marrow function, and ECOG performance status of 0-2. Both drugs were administered intravenously on day 1 of a 21-day cycle. The following doses (mg/m2) of Doxil and cyclophosphamide were tested: 30/500, 40/600, and 48/600. RESULTS: Thirty-seven patients with a median age of 62 years (male:female 21:16) received 119 cycles of Doxil and cyclophosphamide. Hand-foot syndrome and mucositis were the dose limiting toxicities for this combination. Other major toxicities included neutropenia. The side effects to the combination were cumulative. The RPTD of Doxil and cyclophosphamide was 48 mg/m2 and 600 mg/m2, respectively. Three patients with adenocarcinoma of the stomach, fibrosarcoma of the stomach and renal cell carcinoma showed objective antitumor responses. CONCLUSION: The toxicity profile of the combination of Doxil/cyclophosphamide differs significantly from that of non-liposomal doxorubicin plus cyclophosphamide. Major toxicities of the combination include the hand-foot syndrome, stomatitis and neutropenia.

Cellular DNA content parameters as prognostic indicators in human astrocytomas.

OBJECTIVE: Clinical parameters such as grade, size and/or location of the tumor are good predictors of outcome in patients with astrocytoma. The objective of this study was to determine whether DNA content parameters have a prognostic significance for this group of tumors. METHODS: Following optimization and validation of methodology for evaluating cellular DNA content parameters (CDCP), tumor DNA ploidy and percent S phase fraction (SPF) were determined from 64 patients using formalin fixed, paraffin embedded specimens (mean coefficient of variation=4.94) obtained over a 10-year period. Median survival times correlated with grade (I/II=1154 vs. III/IV=483days, P=0.0317). Fifty-five percent of the specimens contained DNA aneuploid (DNA-A) components (average SPF=18.3%) and 45% were DNA diploid (DNA-D) (average SPF=9.6%). Survival did not correlate with overall differences in DNA ploidy (DNA-D=181 vs. DNA-A=206days, P=0.6314) when treated and untreated tumors were analyzed. However, a trend for prolonged median survival was observed in patients whose tumors were untreated with respect to cytotoxic therapy based on DNA ploidy status (DNA-D=275 vs. DNA-A=15days, P=0.3408). Survival for all patients did not correlate with median SPF (<13.5% av.=121 vs. >13.5% av.=154days, P=0.6534). CONCLUSION: DNA content parameters may correlate with the natural history and treatment outcome of newly diagnosed untreated patients with astrocytomas.

A phase II study of carboplatin and paclitaxel in adenocarcinoma of unknown primary.

BACKGROUND: Cisplatin-based combination chemotherapy is commonly used in the treatment of carcinoma of unknown primary site. Paclitaxel has shown promising activity as a single agent in a number of malignancies. This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with adenocarcinoma of unknown primary site (ACUP). METHODS: Twenty-two patients with ACUP were enrolled in the study. Patients were treated with 200 mg/m2 paclitaxel intravenously (IV) over 3 hours followed by carboplatin IV with a targeted plasma area under the curve (AUC) of 5 mg/h/mL. RESULTS: A total of 73 treatment courses were administered with a median of 5 courses per patient. Five of the 22 registered patients had a major response for an objective response rate of 23% (90% confidence interval [CI], 0.11-0.40) by intention-to-treat analysis. The median response duration was 4.1 months (90% CI, 3.6-7.1). The median survival time was 6.5 months (90% CI, 5.5-10.1) and the 1-year survival rate was 27% (90% CI, 0.11-0.42). The major toxicity observed was neutropenia, with grade 3-4 neutropenia occurring in 3 patients (14%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is a tolerable and moderately active regimen in ACUP.

A phase II study of celecoxib, gemcitabine, and cisplatin in advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer is amongst the most chemoresistant malignancies. Expression of the cyclooxygenase-2 (COX-2) enzyme plays a major role in tumor progression and resistance to therapy. A Phase II study was undertaken to determine the effect of gemcitabine by fixed-dose rate infusion (FDR), cisplatin and the COX-2 inhibitor, celecoxib, on the 6-month survival rate in patients with metastatic pancreatic cancer. METHODS: The eligibility criteria included a pathologically or cytologically confirmed diagnosis of adenocarcinoma of the pancreas. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1,000 mg/m(2) over 100 minutes, cisplatin 35 mg/m(2) I.V. on days 1 and 8, and celecoxib continuously at a daily dose of 800 mg. Cycles were repeated every 21 days. RESULTS: Twenty-two patients with metastatic pancreas cancer were enrolled (median age, 59.5 years; M:F, 13:9). The median number of cycles was 2 per patient. The median survival time was 5.8 months (90% CI, 3.6-7.6 months). The probability of survival at 6 months was 46% (90% CI, 27-62%). The major toxicity was neutropenia with grade 3 or 4 toxicities seen in 65% of patients. CONCLUSIONS: The addition of celecoxib to gemcitabine (by FDR) and cisplatin did not appear to increase activity of the chemotherapy doublet in patients with advanced pancreatic cancer. Celecoxib alone may not be sufficient to sensitize pancreatic cancer to the effects of conventional cytotoxic therapy.

Hormone-refractory prostate cancer responding to capecitabine.

A 66-year-old male patient with advanced prostate cancer presented with bony metastases, including pathologic fractures and hepatosplenomegaly. The patient responded to luteinizing hormone-releasing hormone agonists for more than 1 year. A clear progression while taking luteinizing hormone-releasing hormone agonists manifested as a progressive rise in prostate-specific antigen, alkaline phosphatase, hepatosplenomegaly, and myelophthisic pancytopenia. We administered capecitabine for 5 months with a complete clinical response. At last follow-up, the patient's liver function tests and prostate-specific antigen level have normalized. Liver size by computed tomography and blood counts both improved. To our knowledge, no previous case reports of capecitabine in the treatment of prostate cancer have been published.