Biomedical subjects

P A Philip

Publications and source records attributed to P A Philip.

At least 19 recordsLinked to original sources

PubMed2006

Secondary cancers after a lung carcinoid primary: a population-based analysis.

Carcinoid tumors of the lung were first described in 1937, yet little is known about their etiology. The aim of the present investigation was to determine if there was excess risk of secondary cancers in a population-based sample after a lung carcinoid tumor diagnosis which may provide insight to the etiology. Subjects were 1882 cases diagnosed with carcinoid tumors of the lung between 1988 and 2000 whose information was obtained from the Surveillance, Epidemiology and End Results (SEER) Program database. Standardized incidence ratios were calculated by dividing the observed number of second primary cancers by the expected number of cancers. Excess risk of breast cancer was seen following diagnosis of a carcinoid tumor (SIR=1.80 95% CI 1.22-2.55). When stratified by time after diagnosis, excess risk of breast cancers in women was seen in the first 5 years after carcinoid diagnosis (SIR=1.68 95% CI 1.08-2.50) but fewer than expected breast cancers were diagnosed greater than 5 years after carcinoid diagnosis (SIR=0.29 95% CI 0.09-0.68). Prostate cancers also occurred 2.8 times more often than expected (95% CI 1.66-4.43), with risk being elevated only in the first 5 years post-carcinoid diagnosis. Development of lung carcinoids may be the result of genetic predisposition or environmental exposures, particularly those that are hormonally related. The role of genetics and sex hormones in lung carcinoid development, as well as the identification of other risk factors, should be explored.

Breast Neoplasms↗

PubMed2006

Stereoselectivity in metabolism of ifosfamide by CYP3A4 and CYP2B6.

The aim was to identify the hepatic cytochromes P450 (CYPs) responsible for the enantioselective metabolism of ifosfamide (IFA). The 4-hydroxylation, N2- and N3-dechloroethylation of IFA enantiomers were monitored simultaneously in the same metabolic systems using GC/MS and pseudoracemate techniques. In human and rat liver microsomes, (R)-IFA was preferentially metabolized via 4-hydroxylation, whereas its antipode was biotransformed in favour of N-dechloroethylation. CYP3A4 was the major enzyme responsible for metabolism of IFA enantiomers in human liver. The study also revealed that CYP3A (human CYP3A4/5 and rat CYP3A1/2) and CYP2B (human CYP2B6 and rat CYP2B1/2) enantioselectively mediated the 4-hydroxylation, N2- and N3-dechloroethylation of IFA. CYP3A preferentially supported the formation of (R)-4-hydroxyIFA (HOIF), (R)-N2-dechloroethylIFA (N2D) and (R)-N3-dechloroethylIFA (N3D), whereas CYP2B preferentially mediated the generation of (S)-HOIF, (S)-N2D and (S)-N3D. The enantioselective metabolism of IFA by CYP3A4 and CYP2B1 was confirmed in cDNA transfected V79 cells.

Animals↗

PubMed2004

A phase II study of carboplatin and paclitaxel in esophageal cancer.

BACKGROUND: This study was conducted to evaluate the efficacy and toxicity of combination carboplatin and paclitaxel in patients with esophageal cancer. MATERIALS AND METHODS: Thirty-five patients were enrolled. Patients were treated with paclitaxel 200 mg/m(2) intravenously (i.v.) over 3 h and carboplatin i.v. at an AUC of 5 mg/h/ml. Thirty-three patients were assessable for toxicity and objective response. RESULTS: A total of 166 treatment courses were administered with a median of five courses per patient. The objective response rate was 43% [90% confidence interval (CI) 0.3-0.58] by the intention-to-treat analysis. The median response duration was 2.8 months (90% CI 2.1-5.4). The median survival time was 9 months (90% CI 7-13.8) and the 1-year survival rate was 43% (90% CI 0.29-0.57). The major grade 3-4 toxicity observed was neutropenia, occurring in 17 patients (52%). There were no treatment-related deaths. CONCLUSIONS: The combination of carboplatin and paclitaxel is an moderately active and tolerable regimen in advanced esophageal cancer.

Adenocarcinoma↗

PubMed2003

Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer.

PURPOSE: This phase II study was undertaken to determine the efficacy of adding infusional fluorouracil (FU) to the chemotherapy doublet of gemcitabine and cisplatin in patients with advanced pancreatic cancer. PATIENTS AND METHODS: The eligibility criteria included histologically or cytologically confirmed adenocarcinoma of the pancreas that was either unresectable or metastatic. No prior gemcitabine therapy was allowed. Patients received a combination of gemcitabine 1000 mg/m2 intravenously (IV) on days 1, 8, and 15; cisplatin 50 mg/m2 IV on days 1 and 15; and FU 175 mg/m2/d from days 1 to 15 by continuous IV infusion. Cycles were repeated every 28 days. Objective tumor response and toxicity were evaluated according to the World Health Organization criteria. RESULTS: A total of 47 patients (median age, 57 years; males, 59%) were enrolled. Sixteen patients had locally advanced (LA) disease, and 31 patients had metastatic disease. A total of 183 cycles of chemotherapy were administered. In patients with metastatic disease (n = 31), the probability of survival at 6 and 12 months was 66% and 34%, respectively. Objective partial response or stable disease was observed in 26% (90% confidence interval [CI], 0.14 to 0.41) and 61% (90% CI, 0.45 to 0.74) of patients, respectively. In patients with LA disease (n = 16), there were three partial responses (19%; 90 CI, 0.07 to 0.39). One patient in this group was successfully resected after FU-based radiotherapy. The most common grade 3 to 4 toxicities were neutropenia (60%), thrombocytopenia (42%), and anemia (26%). Thirteen patients were hospitalized for treatment-related complications. CONCLUSION: The combination of gemcitabine, cisplatin, and infusional FU has significant activity in patients with advanced pancreatic cancer.

Adenocarcinoma↗

PubMed2003

Developments in the systemic therapy of pancreatic cancer.

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the United States of America. Progress in the treatment of this disease in the past several decades has been very modest. Several new agents with activity against pancreatic cancer have been identified. Of these, gemcitabine is the most promising agent when used in combination with other drugs. Pilot phase II studies combining gemcitabine with 5-flourouracil, irinotecan, docetaxel, or cisplatin show improved outcomes in objective response rates and survival that need to be confirmed in larger randomized studies. Advancement in the understanding of the molecular biology of neoplasia in recent years has helped identify several molecular targets for future new drug development in pancreatic cancer. Assessment of response to therapy of pancreatic cancer has been a difficult challenge. Functional imaging with techniques such as positron emission tomography (PET) may yield a more precise and timely objective evaluation of response to treatment.

Adenocarcinoma↗

PubMed2002

A single-institution experience with concurrent capecitabine and radiation therapy in gastrointestinal malignancies.

PURPOSE: We report our clinical experience with 32 patients receiving concurrent irradiation and capecitabine. METHODS AND MATERIALS: Medical records of patients with gastrointestinal malignancies treated with radiation and capecitabine therapy were reviewed. RESULTS: The population consisted of 20 males and 12 females, with a median age of 67.5 years (45-84 years) and adequate hepatic and bone marrow function. Histology was adenocarcinoma in all patients, except two with esophageal squamous carcinoma. Twenty-one patients received the regimen as adjuvant therapy, three received preoperative therapy, and 8 patients received therapy for palliation. The median dose of capecitabine was 1600 mg/m(2)/day (1200-2500 mg/m(2)/day) orally for 5 days per week for the duration of radiation therapy. Thirty patients received a total dose ranging from 45 Gy to 64 Gy over 4-6 weeks. Two previously radiated patients received total doses of 29.9 Gy and 46 Gy. Grade 3/4 toxicities observed were neutropenia in 3 patients and diarrhea, thrombocytopenia, fatigue, and myocardial infarction in 1 patient each. No treatment-related mortality was observed. Twenty of 21 patients (95.2%) who received adjuvant therapy continue to be in complete remission. Four of 11 (36%) evaluable patients demonstrated a response. CONCLUSION: Concurrent capecitabine and radiation were very well tolerated and warrant further investigation in prospective trials.

Adenocarcinoma↗

PubMed2001

Phase II study of gemcitabine and cisplatin in the treatment of patients with advanced pancreatic carcinoma.

BACKGROUND: Pancreatic carcinoma is considered among the most chemoresistant of human malignancies. The most commonly used cytotoxic single agents, 5-fluorouracil and 2'-deoxy-2',2'-difluorocytidine (gemcitabine), have objective response rates of less than 10% in large studies. Hypothesizing noncross resistance and a synergistic interaction between gemcitabine and cisplatin, early clinical studies have demonstrated significant activity with this combination in patients with several types of malignant disease. A Phase II study was undertaken to determine the efficacy of gemcitabine in combination with cisplatin in patients with locally advanced and metastatic pancreatic carcinoma based on these considerations. METHODS: The eligibility criteria included histologically confirmed, locally advanced, unresectable or metastatic exocrine carcinoma of the pancreas with no prior gemcitabine therapy; prior adjuvant therapy was allowed provided the last day of therapy was at least 6 months prior to starting treatment; clinically measurable or evaluable disease; a Southwest Oncology Group scale performance status of 0-2; a life expectancy of > 12 weeks; and adequate bone marrow, hepatic, and renal function. A total of 42 patients, 4 patients with locally advanced, unresectable disease and 38 patients with metastatic disease, were treated and received a total of 211 cycles of therapy between May 1997 to March 1999. The median age of patients was 61.5 years. The patients were treated in the outpatient setting with a combination of gemcitabine 1,000 mg/M(2) intravenously over 30 minutes administered on Days 1, 8, and 15 of each cycle and cisplatin 50 mg/M(2) intravenously administered after gemcitabine infusion on Days 1 and 15 with adequate prehydration accompanied by adequate urinary output. Cycles were repeated every 28 days. Response and toxicity were assessed according to World Health Organization and standard criteria. RESULTS: The complete and partial response rate among all 42 registered patients was 11 of 42 patients (26%; 95% confidence interval, 0.14-0.42). Stabilization of disease was seen in 15 patients (38%). Two additional patients with metastatic disease who achieved major responses to chemotherapy were rendered free of disease surgically, achieving a complete response status. The median overall survival was 7.1 months (95% confidence interval [CI], 6.3-9.1 months), with 64% of patients alive at 6 months and 19% of patients alive at 12 months. The median time to disease progression was 5.4 months (range, 0.9-20.8 months). Major toxicities were neutropenia and thrombocytopenia, with one episode of neutropenic fever. CONCLUSIONS: The combination of gemcitabine and cisplatin appeared to have significantly greater activity than single-agent gemcitabine in this Phase II study, with tolerable toxicity. The antitumor activity of this combination needs to be confirmed in multi-institutional or comparative trials.

Adult↗

PubMed2001

Bryostatin 1 induces differentiation and potentiates the antitumor effect of Auristatin PE in a human pancreatic tumor (PANC-1) xenograft model.

Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Hence, there is a tremendous need for development of new and effective therapy for this tumor. In an earlier study we reported a potent antitumor activity of Auristatin PE (AuriPE) against pancreatic tumor. In addition, we have also reported that bryostatin 1 (bryo1) induces differentiation of leukemia cells, but the effect of bryo1 has not been investigated in pancreatic tumors. This is the first report where we demonstrate that bryo1 induces differentiation and potentiates the antitumor effect of AuriPE in a human pancreatic tumor (PANC-1) xenograft model. A xenograft model was established by injecting the PANC-1 cells s.c. in severe combined immune deficient (SCID) mice. After development of the s.c. tumors, tumors were dissected and small fragments were transplanted in vivo to new SCID mice, with a success rate of 100% and a doubling time of 4.8 days. The SCID mouse xenograft model was used to test the in vivo differentiation effect of bryo1 and its efficacy when given alone or in combination with AuriPE. Sections from paraffin-embedded tumors excised from untreated (control) SCID mice revealed typical poorly differentiated adenocarcinoma of the pancreas. Interestingly, sections of s.c. tumors taken from bryo1-treated mice revealed carcinomas that were much lower grade and less aggressive, and displayed prominent squamous and glandular differentiation. In this study, the tumor growth inhibition (T/C), activity score and cure rate for bryo1, AuriPE and bryo1+AuriPE were 80%, (+) and 0/4; 0.0%, (++++) and 3/5; and 0.0%, (++++) and 3/4, respectively. Mice treated with either AuriPE or bryo1+AuriPE were free of tumors for more than 150 days and were considered cured. The use of bryo1 as a novel differentiating agent and its combination with AuriPE should be further explored for the treatment of adenocarcinoma of the pancreas.

Animals↗

PubMed2001

Pancreatic cancer: the evolving role of systemic therapy.

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the US. The outcome for patients with pancreatic cancer has not essentially altered over the past few decades. Several new drugs with activity against pancreatic cancer have recently been identified for use in palliative settings. Of these, gemcitabine is the most widely used agent against the disease, but its benefit is very modest. Pilot Phase II studies combining gemcitabine with 5-fluorouracil (5-FU), irinotecan, docetaxel or cisplatin show improved outcomes that need to be confirmed in randomised studies. Concurrent administration of gemcitabine and external beam radiation therapy (EBRT) for locally advanced pancreatic cancer is feasible and is currently undergoing efficacy evaluations. Current research in pancreatic cancer involves newer dosing schedules of gemcitabine, and combinations of gemcitabine with novel agents. Ultimately, better understanding of the molecular biology of pancreatic neoplasia will identify potential cellular targets for future development of new agents for pancreatic cancer.

Animals↗

PubMed2001

A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer.

Current chemotherapy for patients with advanced colorectal cancer is relatively ineffective and may be associated with significant toxicity. Bryostatin 1 (bryo 1) influences cell proliferation, intracellular metabolism and signaling, differentiation, and apoptosis in human cancer cell lines via modulation of protein kinase C (PKC) activity. This trial investigates the efficacy and toxicity of bryo 1 as a novel therapeutic agent for patients with advanced colorectal cancer who have had previous 5-fluorouracil therapy. The primary end point was tumor response to bryo 1. Toxicity was also assessed. Twenty-eight patients with advanced colorectal cancer were enrolled. The mean age was 59 years (range, 38-76), with 16 men and 12 women, and good minority representation (11 African-Americans). The first 10 patients initially received 25 microg/m2 of bryo 1 weekly as a 24-h infusion for 3 weeks of every 4-week cycle, with dose escalation to 35 microg/m2 starting with the second cycle. The remaining patients were started at 35 microg/m2 and escalated to 40 microg/m2, if toxicity was minimal. Twenty-five patients were evaluable for objective tumor response, and complete data on toxicity were collected on 26 patients. No partial or complete tumor responses were observed. All 25 patients had disease progression within four cycles. Myalgia was the most common toxicity. Myelosuppression was not seen. bryo 1 as a weekly 24-h continuous infusion lacks single-agent antitumor activity in advanced colorectal cancer. Toxicity differs from that of traditional chemotherapeutic drugs.

Adult↗

PubMed2000

Biochemotherapy for melanoma.

Systemic therapy for advanced melanoma includes chemotherapy, either with dacarbazine (DTIC) alone or a multiagent combination chemotherapy, and biologic therapy with recombinant interferon-alpha and/or interleukin-2. However, none of these treatment options has produced long-term control of the disease except on rare occasions. Combined chemo-immunotherapy (biochemotherapy) has shown high objective response rates (approximately 50%) and a significant though small proportion of long-term complete responders in metastatic melanoma. It has, however, been associated with greater toxicity. Overall results of sequential versus concurrent biochemotherapy are similar, but the toxicity appears to be less severe in patients treated with the concurrent regimen. At this time, biochemotherapy is under evaluation in a well-designed prospective, randomized trial to identify whether there is benefit to this strategy, compared with chemotherapy alone.

Animals↗

PubMed1999

Use of V79 cells with stably transfected cytochrome P450 cDNAs in studying the metabolism and effects of cytotoxic drugs.

PURPOSE: Studying the metabolism of cytotoxic drugs has become increasingly necessary to predict clinically significant drug-drug interactions and to understand the basis of interindividual variations in the pharmacokinetics of anticancer agents. The aim of this study was to determine the feasibility of using V79 Chinese hamster fibroblasts, which are stably transfected with cytochrome P450 (CYP) cDNAs, to study the metabolism of cytotoxic drugs in vitro. METHODS: The 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine cell survival after incubation with drugs. Gas chromatography/mass spectroscopy was used for the quantitation of metabolites of cyclophosphamide and ifosfamide in culture medium. The coculture technique was used to study the generation of cytotoxic metabolites in culture medium. RESULTS: After treatment with either cyclophosphamide or ifosfamide (100 microM to 1 mM) cytotoxicity was demonstrated in only cytochrome CYP2B1- and cytochrome CYP3A4-expressing cells. Treatment of parental nontransfected cells that were cocultured with CYP-expressing cells with cyclophosphamide resulted in increased sensitivity to this drug. All active and inactive metabolites of cyclophosphamide and ifosfamide were detected in the culture medium. Cyclophosphamide-induced cytotoxicity in CYP2B1- and CYP3A4-expressing cells was abrogated by metyrapone and midazolam/ troleandomycin, respectively. Paclitaxel showed greater cytotoxicity against parental V79 cells than against the CYP2BI-, 2E1-, or 3A4-expressing cells, which was also influenced by cotreatment with CYP inhibitors. CONCLUSIONS: Stable expression of CYP cDNAs by V79 cells provided an in vitro system to study cytotoxic drug metabolism. Cell viability and metabolite assays were used to determine the differential metabolism and effects in different CYP-transfected cell lines treated with cytotoxic drugs. The potential use of this V79 cell expression system is in studying enzymes involved in the metabolism of cytotoxic drugs, especially early in drug development. In addition, this system may be used to determine drug interactions that may influence the outcome of therapy in patients with cancer.

Animals↗

PubMed1999

Phase II study of CI-958 in colorectal cancer.

PURPOSE: We completed a phase II trial of CI-958 (NSC 635371) in patients with advanced colorectal cancer given at a dose of 700 mg/m2 every 21 days. METHODS: All 15 patients had metastatic disease and had been previously treated with one 5-fluorouracil-based regimen in an adjuvant (six) or metastatic (nine) setting. RESULTS: None of the patients treated with CI-958 had an objective response to treatment. Median survival was 4.8 months after the start of treatment. Leukopenia was the major toxicity, but no patient experienced febrile neutropenia. An acute febrile reaction was seen after infusion in four of the first nine patients treated. This was abrogated by pretreatment with dexamethasone in the remaining patients. CONCLUSIONS: CI-958 was not effective at this dose and schedule in patients with previously treated advanced colorectal cancer.

Adenocarcinoma↗

PubMed1999

A phase II study of the modulation of 5-fluorouracil and folinic acid with high-dose infusional hydroxyurea in metastatic colorectal carcinoma.

BACKGROUND: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, may potentiate the activity of 5-fluorouracil (5-FU) and folinic acid (FA) by reducing the deoxyribonucleotide pool available for DNA synthesis and repair. However as HU may inhibit the formation of 5-fluoro-2-deoxyuridine-5-monophosphate (FdUMP), one of the principal active metabolites of 5-FU, the scheduling of HU may be critical. In vitro experiments suggest that administration of HU following 5-FU, maintaining the concentration in the region of 1 mM for six or more hours, significantly enhances the efficacy of 5-FU. PATIENTS AND METHODS: 5-FU/FA was given as follows: days 1 and 2-FA 250 mg/m2 (max. 350 mg) over two hours followed by 5-FU 400 mg/m2 by intravenous bolus (i.v.b.) over 15 minutes and subsequently 5-FU 400 mg/m2 infusion (ivi) over 22 hours. HU was administered on day 3 immediately after the 5-FU with 3 g i.v.b. over 15 minutes followed by 12 g ivi over 12 hours. RESULTS: Thirty patients were entered into the study. Median survival was nine months (range 1-51+ months). There were eight partial responses (28%, 95% CI: 13%-47%). The median duration of response was 6.5 (range 4-9 months). Grade 3-4 toxicities included neutropenia (grade 3 in eight patients and grade 4 in five), anaemia (grade 3 in one patient) and diarrhoea (grade 3 in two patients). Neutropenia was associated with pyrexia in two patients. Phlebitis at the infusion site occurred in five patients. The treatment was complicated by pulmonary embolism in one patient and deep venous thrombosis in another. CONCLUSION: HU administered in this schedule is well tolerated. Based on these results and those of other phase II studies, a randomised phase III study of 5-FU, FA and HU versus 5-FU and FA using the standard de Gramont schedule is recommended.

Adenocarcinoma↗

PubMed1999

A pilot study of increasing dose intensity of epirubicin and ifosfamide in patients with small cell lung cancer by using recombinant granulocyte colony-stimulating factor.

The aim of this prospective study was to investigate the feasibility of increasing the dose intensity of chemotherapy in patients with small cell lung cancer (SCLC) by using recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF). Seventeen previously untreated patients (11 male, 6 female) were treated with ifosfamide (5.0 g/m2) and epirubicin (80 mg/m2) in two successive cohorts. Eight patients received chemotherapy every 2 weeks and r-metHuG-CSF 5 microg/kg given subcutaneously daily for 10 days (cohort A), and nine patients received chemotherapy at 10-day intervals with r-metHuG-CSF 5 microg/kg subcutaneously given daily for 7 days (cohort B). The relative dose intensity compared with the conventional 3-weekly regimen was 1.5 and 2.1 for cohorts A and B, respectively. Neutropenia-associated fever complicated two and five treatment courses in cohorts A and B, respectively. There were five episodes of grade 3/4 thrombocytopenia. There were no treatment delays in cohort A and one cycle was delayed in cohort B. One patient from each cohort was withdrawn due to toxicity. Grade 3/4 non-haematological toxicity, other than alopecia, was not observed. This study confirms that it is feasible to increase the relative dose intensity of ifosfamide and epirubicin in patients with SCLC to 2.1 by using r-metHuG-CSF and shortening the interval between treatment cycles.

Aged↗

PubMed1999

Gemcitabine and UFT plus oral calcium folinate: phase I study.

Gemcitabine (Gemzar) is a nucleoside analog increasingly used in the treatment of a variety of solid tumors. DNA synthesis is inhibited by gemcitabine by masked chain termination and via inhibition of ribonucleotide reductase. Synergy may exist between gemcitabine and other antimetabolites, including 5-fluorouracil. The varying patterns of dose-limiting toxicities to gemcitabine and UFT (uracil and tegafur in a 4:1 molar ratio) plus oral calcium folinate (Orzel) permit their use in combination. The primary aim of this phase I study is to determine the maximum tolerated doses of gemcitabine and UFT plus oral calcium folinate in patients with a variety of solid tumors. Only eight patients have been recruited to date, with myelosuppression being the main toxicity observed.

Aged↗

PubMed1998

Evaluation of pyrazoloacridine in patients with advanced pancreatic carcinoma.

PURPOSE: Pyrazoloacridine (PZA) is an acridine derivative selected for clinical development because of broad pre-clinical antitumor activity and solid tumor selectivity. Phase I evaluations with PZA have demonstrated predictable toxicity and suggested clinical efficacy. A phase II trial in patients with previously untreated advanced pancreatic cancer was conducted. METHODS: PZA was administered at a dose of 750 mg/m2 intravenously over 3 hours every 21 days. Seventeen patients were treated receiving a total of 46 courses of PZA. RESULTS: Of the 15 patients evaluable for response, no responses were observed (0% response rate, 95% confidence interval 0-22%). Major toxicities directly attributable to PZA included moderate neutropenia and mild neurotoxicity. CONCLUSION: PZA at this dose and schedule of administration was inactive in patients with pancreatic carcinoma.

Acridines↗

PubMed1998

Phase I study of the mitomycin C analogue BMS-181174.

BMS-181174 is an aminodisulphide derivative of Mitomycin C (MMC) with activity against a range of tumour cell lines and xenografts, including MMC-resistant tumours. In a phase I study of 82 patients with confirmed malignancy, we administered BMS-181174 at doses of 0.8-75 mg m(-2) by intravenous injection every 28 days. At least three patients were evaluated at each dose level, and 174 courses were administered. The pharmacokinetics were dose linear at BMS-181174 doses of 11.5-75 mg m(-2) and the drug appeared to undergo wide distribution. The maximum-tolerated dose was 65 mg m(-2) in previously treated patients and 75 mg m(-2) in chemotherapy-naive cases. The dose-limiting toxicity was myelosuppression, particularly thrombocytopenia, which was prolonged and cumulative. Three patients treated at 65-75 mg m(-2) died suddenly with evidence of pneumonia/pneumonitis, thought to be drug-related. Other toxicities included thrombophlebitis, possible cardiotoxicity (asymptomatic, reversible decline in left ventricular function) and renal impairment. The partial response rate was 5% (4 out of 82) overall, and 9% (3 out of 32) in patients treated at 65-75 mg m(-2). Responses occurred in treated and previously-untreated patients, including cases of colorectal cancer, non-small-cell lung cancer, ovarian cancer and adenocarcinoma of unknown primary site. BMS-181174 has anti-cancer activity but, because of its toxicity, particularly pneumonitis and thrombophlebitis, no phase II studies are planned.

Adult↗