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Biomedical subjects

D R Spriggs

Publications and source records attributed to D R Spriggs.

At least 19 recordsLinked to original sources
PubMed2005

Phase I trial of bortezomib and carboplatin in recurrent ovarian or primary peritoneal cancer.

PURPOSE: To determine the maximum-tolerated dose, pharmacodynamics, and safety of the combination of bortezomib and carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: Fifteen patients were treated with a fixed dose of carboplatin (area under the curve [AUC] 5) and increasing doses of bortezomib (0.75, 1, 1.3, and 1.5 mg/m2/dose). Patients must have received upfront chemotherapy and up to two prior chemotherapy regimens for recurrent disease. Neurologic evaluation was performed at baseline and after every two cycles by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire and examination by an attending neurologist. All patients received carboplatin alone in cycle 1 to establish baseline pharmacodynamics for nuclear factor-kappa B (NF-kB). Starting with cycle 2, patients were treated with carboplatin on day 1 and bortezomib on days 1, 4, 8, and 11. RESULTS: Diarrhea, rash, neuropathy, and constipation (with colonic wall thickening on computed tomography) were dose-limiting toxicities, occurring in the two patients treated at the 1.5 mg/m2/dose level. The Functional Assessment of Cancer Therapy/Gynecologic Oncology Group neurotoxicity questionnaire was helpful in guiding the need for dose reductions. Neurotoxicity was manageable through six cycles, with appropriate dose reductions. Carboplatin had no effect on bortezomib pharmacodynamics as measured by percent inhibition of the 20S proteasome. Bortezomib decreased carboplatin-induced NF-kB. The overall response rate to this combination was 47%, with two complete responses (CR) and five partial responses, including one CR in a patient with platinum-resistant disease. CONCLUSION: The recommended phase II dose of bortezomib administered in combination with carboplatin (AUC 5) is 1.3 mg/m2/dose.

Aged↗
PubMed2001

Complications associated with intraperitoneal chemotherapy catheters.

PURPOSE: The goal of this work was to determine the complication rate and any predisposing risk factors associated with subcutaneous intraperitoneal (ip) catheters used in the treatment of patients with advanced ovarian cancer. METHODS: We retrospectively reviewed the charts of 301 patients who had a subcutaneous Bardport catheter placed for administration of ip chemotherapy at Memorial Sloan--Kettering Cancer Center (MSKCC) from December 1989 to May 1997. RESULTS: Thirty (10%) patients were identified as having catheter-related complications, with 19 (6.3%) experiencing inflow obstruction and 11 (3.6%) experiencing infection. Only 21 of 301 (7%) required cessation of chemotherapy prior to its expected completion, with 14 (4.6%) occurring in the malfunction group and 7 (2.3%) in the infection group. Three hundred thirteen patients received an ip catheter; however, 12 patients who received their ip chemotherapy elsewhere were excluded when determining the complication rate. Overall, 218 of 313 (69.6%) catheters were placed at the time of laparotomy, 61 of 313 (19.5%) catheters were placed at the time of laparoscopy, and 34 of 313 (10.9%) were placed as a separate procedure. In the malfunction group, 18 of 19 (94.7%) patients had their catheters placed at the time of laparotomy, none were placed at the time of laparoscopy, and 1 of 19 (5.3%) was placed as a separate procedure. In the infection group, 8 of 11 (72.7%) catheters were placed at laparotomy, 2 of 11 (18.3%) were placed at the time of laparoscopy, and 1 of 11 (9.0%) was placed as a separate procedure. Complications occurred in 3 of 54 (5.5%) patients who received platinum alone, 11 of 134 (8.2%) who received platinum in combination, 2 of 43 (4.7%) who received paclitaxel alone, 13 of 61 (21.3%) who received mitoxantrone alone or in combination, and 1 of 9 (11.1%) who received other regimens. CONCLUSION: Subcutaneous ip catheters are associated with a lower rate of catheter-related complications than previously reported, perhaps due in part to both avoiding insertion of ip catheters at the time of bowel surgery and placing ip catheters at the time of laparoscopy.

Antineoplastic Agents↗
PubMed2001

The costs and efficacy of liposomal doxorubicin in platinum-refractory ovarian cancer in heavily pretreated patients.

OBJECTIVE: In clinical practice, chemotherapy agents demonstrating modest second-line activity against platinum-refractory epithelial ovarian cancer (PROC) are frequently used in patients who have received multiple prior chemotherapy agents. Whether the response rates reported in selected patients can be expected in heavily pretreated patients is not known. Similarly, the costs of palliative chemotherapy are not known. We sought to determine the response, survival, and predictors of response in an unselected cohort of PROC patients receiving liposomal doxorubicin (LD) for relapsed disease, and the overall costs of delivering liposomal doxorubicin in this setting. METHODS: In a cohort of 62 consecutive patients who initiated LD as second- or greater-line therapy for PROC, the following variables were examined: age, number of prior regimens for relapse disease, duration of first clinical remission, time from last prior treatment, dose intensity of LD received, response/clinical benefit, time to progression, toxic effects, and survival. Multivariate analyses were used to identify predictors of clinical benefit and overall survival. Direct medical charges were calculated and converted to costs, and major cost drivers determined. RESULTS: Sixty-two patients received a total of 174 cycles of LD. The mean number of cycles per patient was 2 (range, 1-8); the median number of prior regimens for recurrent PROC was 2 (range, 0-8); and the median duration of the first clinical remission was 6 months. Median dose intensity of LD delivered was 11.4 mg/m(2)/week (range, 2.8-16.7 mg/m(2)/week). Nine of sixty-two patients (14.5%) had an objective clinical response by CA-125 and/or CT scan (95% confidence interval, 6-23%). Grade 3/4 toxicity occurred in 11% of patients. In the full cohort, median time to progression was 2.2 months, and median overall survival, 9.6 months (range, 0.2-26 months). Dose intensity was the only independent predictor of overall response. Duration of first clinical remission and number of prior salvage regimens were associated with longer overall survival. The mean total direct medical cost per cycle of LD was $5763, and the major cost drivers were hospitalizations and drug acquisition/delivery costs. CONCLUSION: LD is an active agent in PROC, even when used as greater-than-second-line therapy. Among heavily pretreated patients, delivering a dose intensity of at least 9.0 mg/m(2)/week was associated with a higher probability of response. The cost per cycle of LD is driven by hospitalizations and drug acquisition/delivery costs.

Adult↗
PubMed2001

New drugs in gynecologic cancer.

The implementation of new drug treatments has improved the prognosis for advanced cancers of the cervix, uterus, and ovary. Platinum analogs are the most effective drugs in the treatment of ovarian cancer. Other drugs, such as oxaliplatin, have been proposed as a rational treatment of platinum refractory ovarian cancer. Epothilones are also being studied in clinical trials, as are histone deacetylase inhibitors. Several promising agents may soon receive Food and Drug Administration approval.

Aminopyridines↗
PubMed2000

Intraperitoneal cisplatin and intravenous paclitaxel in the treatment of epithelial ovarian cancer patients with a positive second look.

OBJECTIVE: The aim of this study was to review the role and safety of intraperitoneal (IP) cisplatin and intravenous (IV) paclitaxel in platinum-sensitive epithelial ovarian cancer patients who were found to have small-volume disease (<1 cm) at the time of their second-look procedure. METHODS: In a retrospective review, 32 patients with small-volume disease had an IP Bardport catheter placed at the time of second look at Memorial Sloan-Kettering Cancer Center (1995-1998). Patients received IP cisplatin (75 mg/m(2)) every 3 weeks and either IV paclitaxel (135 mg/ m(2)) every 3 weeks or IV paclitaxel (80 mg/m(2)) weekly for a maximum of five cycles. RESULTS: Twenty-four (75%) of 32 patients received IP cisplatin/IV paclitaxel every 3 weeks and 8 (25%) received IP cisplatin every 3 weeks with weekly IV paclitaxel. Seven (21.9%) of 32 patients required interruption of treatment secondary to neuropathy. Of these, 4 (15.6%) were changed to another IV chemotherapeutic agent, and 3 (9.3%) required discontinuation of IV paclitaxel only. Two (6%) patients required IP port removal secondary to malfunction and were changed to IV therapy and 1 (3%) requested discontinuation of IP therapy secondary to abdominal pain. Median follow-up was 19 months (mean, 20.1 months; range, 6-36 months). Progression of disease after completion of IP therapy was documented by clinical exam, abnormal CT, and/or rising CA-125 levels. The median progression-free interval was 13 months (mean, 15.1 months; range, 2-33 months). Median overall survival was 27 months (mean, 34.2 months; range, 10-42 months). At the time of review, 13 (40.6%) of the 32 patients were alive with disease, 7 (21.9%) were without evidence of disease, and 12 (37.5%) were dead of disease. CONCLUSION: IP cisplatin in combination with IV paclitaxel appears to be no more effective than other reported regimens as second-line therapy for patients with persistent small-volume disease. Neurotoxicity is dose limiting, and the combination cannot be recommended for the routine care of persistent peritoneal cancers.

Adult↗
PubMed1999

Efficacy of live, attenuated, human rotavirus vaccine 89-12 in infants: a randomised placebo-controlled trial.

BACKGROUND: Rotavirus is the most common cause of severe, dehydrating diarrhoea in infants worldwide. We assessed the safety, immunogenicity, and efficacy of a live, oral human rotavirus vaccine, 89-12, in US children in a randomised, placebo-controlled, double-blind multicentre trial. METHODS: 215 healthy infants were enrolled, of whom 213 were given two doses of 89-12 (containing 1x10(5) plaque-forming units) or placebo, and 213 were followed up through one rotavirus season. The frequency of side-effects was compared for 7 days after each dose of vaccine. Immune responses to rotavirus were assessed by serum and stool IgA, and by serum 89-12 neutralising titres. The primary outcome variable (protection from rotavirus disease) was evaluated by comparing the frequencies of rotavirus gastroenteritis in an intention-to-treat analysis. FINDINGS: Adverse reactions were mild. Low-grade fever (> or = 38.1 degrees C) after the first dose was the only side-effect significantly more common in the vaccine group than in the placebo group (21 [19%] vs 5 [5%], p=0.001). An immune response to vaccine was detected in 94.4% of vaccinees. Rotavirus disease occurred in 18 of 107 placebo recipients and two of 108 vaccine recipients (vaccine efficacy 89.0% [95% CI 65.4-94.5]). Ten infants in the placebo group but none in the vaccine group were presented for medical care. INTERPRETATION: The 89-12 rotavirus vaccine was safe and immunogenic and provided a high degree of protection against rotavirus disease. Further investigations of this vaccine are needed to confirm these findings in other settings.

Administration, Oral↗
PubMed1999

Phase I clinical and pharmacokinetic study of an one-hour infusion of ormaplatin (NSC 363812).

Ormaplatin (NSC 363812, tetraplatin) is a stable platinum (IV) analog which has exhibited activity against cisplatin-resistant cell lines. A phase I trial of ormaplatin administered as a 1-h infusion every 4 weeks was performed. Forty-one patients received 101 cycles of drug over the dose range 4-128 mg/m2. The dose-limiting toxicity was reversible thrombocytopenia and granulocytopenia. Minimal myelosuppression was observed at dose levels < or = 78 mg/m2, while grade 3 or 4 myelosuppression (thrombocytopenia and/or granulocytopenia) was seen in 4/8 patients at 98 mg/m2 and 4/5 patients at 123 mg/m2. Nausea and vomiting was observed at all dose levels but was controlled with antiemetic premedication. Neurotoxicity was observed in 5/41 patients and the incidence appeared related to cumulative dose rather than to dose level or drug clearance. Platinum was measured by furnace atomic absorption spectrophotometry. Ormaplatin-derived plasma ultrafilterable platinum (UF-Pt) exhibited linear pharmacokinetics over the dose range studied. The mean total body clearance of UF-Pt was 135 ml/min/m2 and the mean elimination half-life (t1/2beta) was 13.6 h. Ormaplatin exhibited a high degree of protein binding, with more than 70% of platinum protein bound by the end of the infusion. Urinary excretion of platinum accounted for 37% of the total dose of ormaplatin in 24 hours. A phase II dose of 98 mg/m2 is recommended for testing in a patient population with cisplatin-refractory disease.

Adult↗
PubMed1999

Primary intravenous paclitaxel and platinum chemotherapy for high-risk Stage I epithelial ovarian carcinoma.

OBJECTIVE: To evaluate the efficacy of intravenous (i.v.) paclitaxel and platinum chemotherapy in patients with high-risk Stage I epithelial ovarian carcinoma. METHODS: We performed a retrospective chart review of all patients with Stage I ovarian cancer treated at our institution between March 1993 and June 1995. RESULTS: Twenty patients received adjuvant paclitaxel-containing chemotherapy for Stage I ovarian carcinoma after comprehensive surgical staging. Five patients (25%) had Stage IA disease and 15 patients (75%) had Stage IC disease. Tumor grades were: 1, five patients (25%); 2, nine patients (45%); and 3, six patients (30%). Histologic cell types were: clear-cell, ten (50%); endometrioid, five (25%); mucinous, three (15%); and serous, two (10%). Nineteen patients (95%) were treated with i.v. paclitaxel and platinum chemotherapy. One patient (5%) received i.v. paclitaxel alone. Eighteen patients (90%) had five cycles of chemotherapy, while two patients (10%) had three. The 96 total cycles were associated with nine episodes (9%) of significant toxicity: fever, four (4%); severe nausea and vomiting, two (2%); Clostridium difficile enteritis, one (1%); congestive heart failure, one (1%); and anemia, requiring blood transfusion, one (1%). With a median follow-up of 36 months (range 24-50 mos), all 20 patients are alive, and 19 (95%) are disease-free. The one patient (5%) treated with i.v.++paclitaxel alone developed an abdominal recurrence 22 months after diagnosis. CONCLUSION: Primary i.v.++paclitaxel and platinum chemotherapy in patients with high-risk Stage I epithelial ovarian carcinoma is reasonably well tolerated and may improve survival. Larger studies with long-term follow-up are needed.

Adenocarcinoma↗
PubMed1998

BRCA1 up-regulation is associated with repair-mediated resistance to cis-diamminedichloroplatinum(II).

We sought to identify novel genes associated with cis-diamminedichloroplatinum(II) (CDDP) resistance, and by differential display analysis, we found that the human breast and ovarian cancer susceptibility gene BRCA1 was overexpressed in CDDP-resistant MCF-7 cells. A recent report that BRCA1 and human Rad51 colocalize in S-phase cells suggests a role for BRCA1 in DNA damage repair. We hypothesized that BRCA1 plays a role in DNA damage repair-mediated CDDP resistance. In CCDP-resistant variants of breast and ovarian carcinoma cell lines, MCF-7 CDDP/R and SKOV-3 CDDP/R, we found increased levels of BRCA1 protein, and we determined that the SKOV-3 CDDP/R cell line is significantly more proficient at DNA damage repair. Antisense inhibition of BRCA1 in this cell line resulted in an increased sensitivity to CDDP, a decreased proficiency of DNA repair, and an enhanced rate of apoptosis. These data support the hypothesis that BRCA1 is a gene involved in DNA damage repair.

Breast Neoplasms↗
PubMed1998

Lisofylline sensitizes p53 mutant human ovarian carcinoma cells to the cytotoxic effects of cis-diamminedichloroplatinum (II).

A novel approach to counteracting drug resistance is the development of nontoxic agents that are able to preferentially increase the sensitivity of tumor cells to the cytotoxicity of chemotherapy. The possibility that such an agent could be directed specifically against p53-defective tumor cells led us to study the new methylxanthine, Lisofylline, for its ability to sensitize ovary cancer cells to cis-diamminedichloroplatinum(II) (CDDP). In cell lines lacking functional p53 (SKOV3, SKOV3 CDDP-resistant, OVCAR3, and OVCAR432) Lisofylline (20-100 microM) enhanced the cytotoxicity of CDDP by approximately 50% as measured by the Alamar blue vital dye indicator assay. LSF had no effect on p53 wild-type cell lines: OVCAR 420, 429, and 433. Restoration of wild-type p53 phenotype by transfection of SKOV3 cells with a p53 cDNA expression vector showed reversal of sensitization by Lisofylline to CDDP cytotoxicity. While sensitization to DNA damaging agents by other methylxanthines is related to an abrogation of G2 delay, FACS data found no loss of CDDP-induced G2 block in the cell lines, demonstrating that Lisofylline enhanced sensitization. Cell death was examined by quantitative fluorescence microscopy but no increase in apoptosis attributable to Lisofylline exposure was observed. Our results show that the combination of CDDP and Lisofylline preferentially sensitizes p53-defective cancer cells to the cytotoxic effect of CDDP by a yet undetermined mechanism.

Adjuvants, Immunologic↗
PubMed1998

Gastrointestinal toxicity and Clostridium difficile diarrhea in patients treated with paclitaxel-containing chemotherapy regimens.

OBJECTIVE: The objective of this study was to determine the incidence of grade 3 and 4 gastrointestinal toxicity and the prevalence of Clostridium difficile-associated diarrhea (CDAD) in patients with gynecologic malignancies treated with paclitaxel-based chemotherapy regimens. METHODS: We retrospectively reviewed the medical records of all patients treated on the Gynecology Service at Memorial Sloan-Kettering Cancer Center from January 1, 1993 to July 1, 1996. We identified all patients treated with paclitaxel during this period and determined the total number of patients hospitalized for symptoms of gastrointestinal toxicity, including nausea, vomiting, diarrhea, and dehydration, within 4 weeks of chemotherapy, as well as the incidence of CDAD among these patients. RESULTS: Six hundred and twenty-four patients were treated with paclitaxel-containing chemotherapy regimens during the study period, including 55 patients who were treated on a "dose-dense" high-dose protocol for advanced ovarian cancer. Among these, 149 patients (24%) were hospitalized for symptoms of gastrointestinal toxicity. During the study period, a total of 40 cases of CDAD were reported among hospitalized patients on the Gynecology Service and 24 (60%) of these cases occurred in patients who had received paclitaxel within the prior 4 weeks. CONCLUSIONS: The occurrence of CDAD in patients receiving paclitaxel-containing chemotherapy is not rare and can result in severe dehydration requiring hospitalization. The risk of C. difficile colitis appears to be 2.2% in patients receiving standard-dose regimens and as high as 20% in patients receiving high-dose regimens. This etiology should be considered and treated early in patients presenting with symptoms of gastrointestinal toxicity subsequent to chemotherapy treatments.

Anti-Bacterial Agents↗
PubMed1998

Safety and immunogenicity of live, attenuated human rotavirus vaccine 89-12.

The safety and immunogenicity of an orally administered live human rotavirus vaccine candidate (89-12), attenuated by 33 passages in monkey kidney cells, were evaluated in placebo-controlled trials in adults, children and infants. This strain was selected because natural infections with 89-12-like rotaviruses provided 100% protection over two years. The initial evaluations in adults, seropositive children and nine infants indicated that the vaccine was safe. Two doses of vaccine (10(5) p.f.u. dose-1) or placebo were then given to 42 infants, aged from 6 to 26 weeks. No significant difference in side effects was seen. Seroconversion was demonstrated in 19 of 20 previously uninfected vaccine recipients, but > or = 4-fold rises in 89-12 neutralizing antibody titers were detected in only seven subjects. Intestinal IgA responses were detected in 15 subjects. This attenuated human rotavirus was safe and immunogenic and should be further evaluated as a vaccine candidate.

Adult↗
PubMed1998

Phase II study of "dose-dense" high-dose chemotherapy treatment with peripheral-blood progenitor-cell support as primary treatment for patients with advanced ovarian cancer.

PURPOSE: We performed a pilot phase II study to evaluate the potential for delivery of rapidly sequenced high-dose chemotherapy treatments rescued with autologous peripheral-blood progenitor cells (PBP) in patients with previously untreated, advanced ovarian cancer. PATIENTS AND METHODS: A single cycle of mobilization was used, primed with cyclophosphamide (CPA)/paclitaxel (Txl) and filgrastim (granulocyte colony-stimulating factor [G-CSF]), followed by three cycles of high-dose carboplatin (CBDCA)/Txl and one cycle of high-dose melphalan (MEL), each rescued by PBP. We then analyzed the outcome for a total of 56 consecutive patients treated with high-dose chemotherapy as part of this program. RESULTS: In the phase II pilot, 21 patients were enrolled. There were no treatment-related deaths through 98 high-dose treatments, although 34 treatments were complicated by hospitalization, primarily for neutropenic fever. Seventy-six percent of patients experienced grade 3 to 4 gastrointestinal toxicity and 62% experienced grade 2 to 3 neuropathy. Five of 15 (33%) patients who underwent second-look surgery attained a pathologic complete response. In the overall analysis, 56 patients were reviewed. Forty-four patients were assessable for response by second-look surgery or clinical progression. Fifteen of 44 patients achieved a pathologic complete response (34%). The pathologic complete response rate in optimal-disease patients was 12 of 22 (55%), while only three of 22 (13%) suboptimal stage III and IV patients achieved a pathologic complete response. CONCLUSION: The Gynecologic Oncology Group has initiated a pilot phase II trial of this approach in patients with optimally debulked stage III ovarian cancer. There is no evidence to support the use of this or other aggressive regimens outside of a clinical trial.

Adult↗
PubMed1997

Posttranscriptional regulation of protein expression in human epithelial carcinoma cells by adenine-uridine-rich elements in the 3'-untranslated region of tumor necrosis factor-alpha messenger RNA.

Eukaryotic mRNAs contain 3'-untranslated regions (UTR) that are involved in posttranscriptional control of gene expression. AU-rich octanucleotide repeats, UUAUUUAU, present in the 3'-UTR of mature lymphokine and other cytokine transcripts, have been implicated in the regulation of mRNA stability and translational efficiency. For example, previous evidence suggests that the AU-rich element (ARE) present in the 3'-UTR of murine tumor necrosis factor-alpha (TNF-alpha) can affect the posttranscriptional regulation of murine TNF-alpha gene expression in hematopoietic cells. Although cytokines are produced in epithelial cells, little is known about the regulation of TNF-alpha and other cytokine gene expression by 3'-UTR elements in human malignant epithelial cells. To better understand the function of the 3'-UTR of the human TNF-alpha gene in the regulation of TNF-alpha protein production in human epithelial cancer cells, a series of luciferase reporter constructs with portions of the 3'-UTR of human TNF-alpha was transfected into human breast carcinoma cell lines ZR-75-1 and ZR-75-1R (which overexpresses TNF-alpha). The 3'-UTR of TNF-alpha markedly suppressed luciferase activity in both cell lines, and the suppression of activity was reversed by deletion of the AU-rich sequences. This suppression was quantitative, with six repeats causing more inhibition than two repeats. Increased levels of luciferase activity were observed 3 h after TNF-alpha stimulation in ZR-75-1 cells transfected by constructs containing AU-rich repeats. In addition, cytoplasmic extracts from both cell lines were assayed for factors that bind to the 3'-UTR of human TNF-alpha mRNA. RNA-protein binding activities were found in both cell lines. Competition studies showed that these proteins specifically bound to AU-rich repeats present in the 3'-UTR of TNF-alpha. No binding activity was observed when the AU-rich repeats were deleted. TNF-alpha exposure markedly increased activity of several RNA-binding proteins, especially a novel Mr 50,000-55,000 RNA-binding protein. The binding activity in untreated ZR-75-1R was higher than that in untreated ZR-75-1 cells, suggesting that the level of RNA-protein binding correlates with the expression level of TNF-alpha in human epithelial cancer cells and that the RNA-binding proteins may control expression of TNF-alpha in ZR-75-1 cells. We conclude that the AU-rich repeats in the 3'-UTR of human TNF-alpha mRNA may regulate gene expression in human epithelial cancer cells by binding to AU sequence-specific proteins, including a previously undescribed Mr 50,000-55,000 protein not observed in hematopoietic cells.

Animals↗
PubMed1997

Phase I study of tirapazamine and cisplatin in patients with recurrent cervical cancer.

OBJECTIVES: Tirapazamine (SR 4233) is a benzotriazine compound exhibiting substantial differential toxicity for hypoxic cells. A large enhancement in tumor cell killing has been demonstrated in preclinical studies when tirapazamine was combined with cisplatin. This phase I study was undertaken to establish a safe dose combination of tirapazamine and cisplatin when administered to patients with recurrent cervical carcinoma. METHODS: Tirapazamine was administered as an intravenous infusion over 2 hr, followed 1 hr later by cisplatin intravenously over 1 hr, every 21 days. All patients received prophylactic antiemetics consisting of ondansetron, dexamethasone, and lorazepam. The planned dose escalation levels of tirapazamine were 195, 260, 330, and 390 mg/m2. The cisplatin dose was fixed at 75 mg/m2. RESULTS: A total of 12 patients were treated with 43 courses of therapy. Patients were heavily pretreated. Eleven of the 12 had prior radiotherapy and 5 of the 12 had prior cisplatin-based chemotherapy. A maximally tolerated dose of 330 mg/m2 was defined for this patient population. The dose-limiting toxicity was nausea and vomiting. All 12 patients were also evaluated for response. Two major responses were seen (17%). In addition, there were three minor responses (25%) and 4 patients achieved disease stabilization (33%). All major and minor responses were seen at the highest dose level tested of 330 mg/m2. CONCLUSIONS: Tirapazamine and cisplatin is an interesting drug combination in the treatment of cervical cancer. Phase II testing is planned.

Adult↗
PubMed1997

Dose escalation of paclitaxel with high-dose carboplatin using peripheral blood progenitor cell support in patients with advanced ovarian cancer.

A phase I study of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given in combination with high-dose carboplatin was conducted to identify the antitumor efficacy and maximum tolerated dose of paclitaxel in patients who had received sequential cycles of paclitaxel/cyclophosphamide as prior treatment for ovarian carcinoma. Eighteen patients with advanced ovarian cancer were treated in this study. Induction therapy consisted of two cycles of cyclophosphamide 3.0 g/m2 plus high-dose paclitaxel 300 mg/m2 plus filgrastim and leukapheresis to harvest peripheral blood progenitor cells, followed by four courses of rapidly cycled high-dose carboplatin with planned dose escalation of paclitaxel (150, 200, 250, and 300 mg/m2) rescued with peripheral blood progenitor cells. The study was amended after accrual of 11 patients, and the remaining seven patients received a single cycle of induction therapy with paclitaxel/cyclophosphamide, followed by four courses of rapidly cycled high-dose carboplatin with planned dose escalation of paclitaxel through levels 200 and 250 mg/m2. All 18 patients have completed therapy. Of the 15 who are evaluable for response, the pathologic complete response was 33% (five of 15 patients). The administration of escalating doses of paclitaxel in combination with high-dose carboplatin following sequential cycles of paclitaxel/cyclophosphamide induction resulted in significant nonhematopoietic toxicity. Induction with a single cycle of paclitaxel/cyclophosphamide resulted in excellent progenitor cell mobilization, and significantly ameliorated the toxicity of this approach. The response rates thus far obtained are promising and warrant further evaluation.

Adult↗
PubMed1997

UCN-01 in ovary cancer cells: effective as a single agent and in combination with cis-diamminedichloroplatinum(II)independent of p53 status.

Our goal was to determine the cytotoxicity of 7-OH-hydroxystaurosporine (UCN-01) as a single agent and in combination with cis-diamminedichloroplatinum(II) (CDDP) in a panel of ovarian carcinoma cells. We sought to examine the role of p53 gene function and alterations in cell cycle progression or other mechanisms of action of UCN-01 including perturbation of the apoptosis pathway mediated by NF-kappaB and Bcl-2/Bax. Cytotoxicity was determined from dose-response curves established by the Alamar blue vital dye indicator assay. Restoration of wild-type p53 in a p53 null cell line, SKOV 3, was achieved by transfection of a p53 expression vector. Cell cycle distribution was measured by fluorescence-activated cell sorting analysis of ethidium bromide-stained nuclei. Apoptosis was measured by quantitative fluorescence microscopy. NF-kappaB DNA binding activity was measured by electrophoretic mobility shift assay. Bcl-2 and Bax levels were determined by Western immunoblotting. UCN-01 was effective as a cytotoxic agent alone and in combination with CDDP in all cell lines studied, regardless of p53 status. The degree of sensitization to CDDP conferred by UCN-01, however, was found to correlate with p53 gene status. p53 wild-type cells seem to be more sensitive to the cytotoxic effects of the combination of UCN-01 + CDDP than the p53 mutant cells. This was confirmed in cells in which p53 wild-type function was restored by transfection of p53 cDNA, but these cells are also significantly more sensitive to CDDP alone. The effects of UCN-01 on cell cycle progression also appear to be p53 dependent but may not be the primary mechanism of action. The rate of apoptosis is increased 4-fold in UCN-01 + CDDP-treated cells compared to either agent alone. UCN-01 does not effect NF-kappaB DNA binding activity or Bcl-2 and Bax levels. UCN-01 enhances CDDP cytotoxicity and apoptosis in ovary cancer cells. This occurs regardless of p53 status, but wild-type p53 seems to increase the degree of sensitization.

Alkaloids↗