Mitomycin C toxicity and pharmacokinetics in mice given sulfur nucleophiles.

The sulfur nucleophiles, sodium thiosulfate (Na2S2O3) and N-acetylcysteine (NAC) given in maximally tolerated doses did not reduce the hematologic toxicity of high dose mitomycin C (MMC) in normal mice. In addition, neither sulfur nucleophile significantly altered the antileukemic activity of MMC. Pharmacokinetic studies of MMC in normal mice, demonstrated rapid plasma elimination (T1/2 beta = 0.

Second-look laparotomy in epithelial ovarian carcinoma. Prognostic factors associated with survival duration.

This article that reports on 70 consecutive patients is one of only a few studies of advanced ovarian cancer that have attempted to define predictive factors associated with survival duration after second-look laparotomy. As in many other investigations, several factors have been analyzed for predicting second-look outcome. The prognostic variables analyzed in this study included age, stage, histologic grade, residual disease status after initial surgery, and type (cisplatin versus no cisplatin) and number of cycles of chemotherapy.

Intraperitoneal mitomycin C in the treatment of peritoneal carcinomatosis following second-look surgery.

Persistent or recurrent peritoneal carcinomatosis (PC) documented at second-look surgery has proved relatively refractory to second-line therapy. The majority of these tumors do not respond to cisplatin based chemotherapy. Because of the relatively high response rate we observed with systemically administered mitomycin C plus 5-fluorouracil, we initiated a trial of intraperitoneal (IP) mitomycin C (10 mg/m2 in 2 L dialysate fluid every 4 weeks) in 14 patients with refractory PC secondary to gynecologic malignancies.

Phase II trial of mitomycin C plus 5-FU in the treatment of drug-refractory ovarian cancer.

Following cisplatin combination chemotherapy for advanced epithelial type ovarian cancer, response to subsequent treatments has proved relatively poor. Mitomycin C and 5-fluorouracil (5-FU) have both been reported to have useful activity as single agents in patients with drug-refractory ovarian cancer. We have carried out a phase II trial of a combination of these two agents in 25 patients who had previously received a median of two chemotherapy regimens (range, one to five regimens).

A phase II trial of mitomycin, vincristine, bleomycin, and cisplatin (MOBP) as neoadjuvant therapy in high-risk cervical carcinoma.

Twenty patients with locally advanced or metastatic cervical carcinoma were treated with mitomycin, vincristine, bleomycin, and cisplatin (MOBP), prior to radiotherapy (RT) of curative intent. Five patients had stage I disease, 2 stage II, 10 stage III, and 3 stage IV. All but one patient with stage I and II disease had nodal metastases.

Treatment of advanced squamous cell carcinoma of the head and neck with isotretinoin: a phase II randomized trial.

Retinoids, the analogs of vitamin A, are active in vitro and in vivo against squamous cell carcinoma in animals and against certain epithelial precancers and cancers in humans. These data led us to design a prospective, multi-institutional, randomized phase II trial of isotretinoin in advanced head and neck squamous cell carcinoma. We randomly assigned 40 patients to receive isotretinoin or methotrexate, the best-studied and most active single agent for this disease.

Cytogenetic and phenotypic analysis of a human colon carcinoma cell line resistant to mitoxantrone.

A human colon carcinoma cell line selected for a 21-fold resistance to mitoxantrone was cross-resistant to the anthracycline, doxorubicin, but not to the anthracene, bisantrene. A 2-fold resistance was observed with vinblastine, another drug associated with multidrug resistance. Net intracellular mitoxantrone and doxorubicin accumulation were decreased at 1 h for all dose levels in the resistant cell line compared to the sensitive cell line.

Phase II study of fludarabine phosphate (NSC-312887) in patients with advanced ovarian cancer. A Southwest Oncology Group Study.

Fourteen evaluable patients with advanced ovarian cancer refractory to one prior chemotherapy regimen were treated with a 5-day schedule of fludarabine phosphate. No responses were noted. The major toxicity was granulocytopenia with 50% of patients having granulocyte counts of less than 1,000/microliter.

Ornithine decarboxylase activity in Barrett's esophagus: a potential marker for dysplasia.

Ornithine decarboxylase activity is known to be increased in certain premalignant conditions. We determined the activity of this enzyme in mucosal biopsy specimens from 15 patients with Barrett's esophagus. Ornithine decarboxylase was greater in Barrett's mucosa than in squamous esophageal or gastric mucosa.

Potentiation of platinum analogue cytotoxicity by hyperthermia.

Carboplatin and iproplatin, two new analogues of cisplatin, appear to have comparable activity in the treatment of advanced ovarian cancer, but minimal nephro- and neurotoxicities. Hyperthermia can potentiate the cytoxicity of cisplatin in vitro and in vivo, but systemic treatment with the combination has proven unsafe in patients. To provide the rationale for an alternative approach, we evaluated the relative degree of additivity between hyperthermia and the three platinum analogues in vitro against a human ovarian adenocarcinoma cell line, UACC-66.

Pharmacokinetics and metabolism of retinol administered at a chemopreventive level to normal subjects.

Thirteen subjects between the ages of 50 years and 70 years were administered a daily 25,000 IU dose of retinol for 9 months. Two subjects experienced mild skin dryness, headaches, and/or alopecia. There were no significant changes in serum chemistries.

Quantitation of ellipsoid tumor areas using a circumferential measuring device.

A controlled trial of a new circumferential area measuring device, the Tumorimeter, was performed on a set of 30 radiographs of chest nodules ranging in size from 1.5 to 5.0 cm diameter.

Efficacy of sodium thiosulfate as a local antidote to mechlorethamine skin toxicity in the mouse.

The highly vesicant nature of the alkylating anticancer agent mechlorethamine (HN2, or nitrogen mustard) requires careful i.v. technique during its administration.

Toxicity of H2-receptor antagonists to isolated rat hepatocytes: structure-activity relationships.

Oxmetidine is a potent and specific antagonist of the histamine H2-receptor. Oxmetidine is also cytotoxic to isolated rat hepatocytes through inhibition of mitochondrial oxidative phosphorylation. The purpose of this investigation was to test a variety of H2-receptor antagonists that are structural analogs of oxmetidine in an attempt to identify a critical structural component or a physicochemical property of the molecule which may be responsible for cytotoxicity.

Role of glutathione reductase during menadione-induced NADPH oxidation in isolated rat hepatocytes.

Metabolism of menadione (2-methyl-1,4-naphthoquinone) results in the rapid oxidation of NADPH within isolated rat hepatocytes. The glutathione redox cycle is thought to play a major role in the consumption of NADPH during menadione metabolism, chiefly through glutathione reductase (GSSG-reductase). This enzyme reduces oxidized glutathione (GSSG), formed via the glutathione-peroxidase reaction, with the concomitant oxidation of NADPH.

Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study.

Cisplatin has proven to be the most active single agent in the treatment of metastatic and recurrent squamous cell cancer of the cervix. In a previous southwest Oncology Group (SWOG) pilot study, the addition of cisplatin to a mitomycin-C, vincristine, and bleomycin (MVB) regimen resulted in a relatively high percentage of durable complete responses. To gain more experience with cisplatin-based chemotherapy regimens, the SWOG initiated a phase II randomized trial of cisplatin, mitomycin-C plus cisplatin (MC), and MVB plus cisplatin (MVBC) in 119 patients with advanced squamous cell cancer of the cervix and no prior chemotherapy exposure.

The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. II. Triethylphosphine gold chloride-induced alterations in mitochondrial function.

Triethylphosphine gold complexes have therapeutic activity in the treatment of rheumatoid arthritis. Many of these compounds are also highly cytotoxic in vitro to a variety of tumor and non-tumor cell lines. Triethylphosphine gold chloride (TEPAu) is highly cytotoxic to isolated rat hepatocytes at concentrations greater than 25 microM.

The mechanism of acute cytotoxicity of triethylphosphine gold(I) complexes. I. Characterization of triethylphosphine gold chloride-induced biochemical and morphological changes in isolated hepatocytes.

Triethylphosphine gold complexes are effective therapeutic agents used for the treatment of rheumatoid arthritis. Many of those molecules are also highly cytotoxic in vitro and can inhibit DNA and protein synthesis. Preliminary experiments have indicated that triethylphosphine gold chloride (TEPAu) may induce the peroxidative decomposition of cellular membrane lipids.

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study.

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over 5 days at a starting dose of 1.7 mg/m2/day every 3 weeks.

New antitumor agents containing the anthracene nucleus.

A series of 21 new compounds related to bisantrene was synthesized and tested in vitro by using clonogenic assays against a variety of human tumor cell lines, fresh human tumors, and P-388 leukemia. Those most closely related to bisantrene were less active than it was, but a subset of compounds with saturated side chains containing two basic nitrogens showed good activity. Two compounds of this subset, N,N'-bis[2-(dimethylamino)ethyl]-9,10-anthracenebis(methylamine)(6 ), and N,N'-bis(1-ethyl-3-piperidinyl)-9,10-anthracenebis(methylamine)(19 ), were very active in vitro against human tumor cell lines, but not active against fresh human tumors or P-388 leukemia cells.

Menadione-induced oxidative stress in hepatocytes isolated from fed and fasted rats: the role of NADPH-regenerating pathways.

Isolated hepatocytes were prepared from fed and fasted rats and exposed to a range of menadione (2-methyl-1,4-naphthoquinone) concentrations. Menadione (300 microM) caused a rapid decline in the (NADPH)/(NADPH + NADP+) ratio from 0.85 to 0.

Phase II trial of vinblastine in previously treated patients with ovarian cancer: a Southwest Oncology Group Study.

Sixty-eight patients with relapsing, epithelial type ovarian carcinoma were entered into a Phase II study of vinblastine. Vinblastine was administered as a continuous intravenous infusion over five days at a starting dose of 1.7 mg/m2/day every 3 weeks.

Tamoxifen therapy in recurrent epithelial ovarian carcinoma.

Thirty-seven patients with recurrent epithelial ovarian carcinoma were entered into a trial of tamoxifen therapy (10 mg BID) to determine the effect on long-term survival. Thirty-one patients were evaluable with follow-up ranging from 6 to 42 months since initiation of hormonal therapy. All patients were heavily pretreated with multiple chemotherapeutic regimens (median 3).

Neoadjuvant therapy for advanced head and neck cancer with allopurinol-modulated high dose 5-fluorouracil and cisplatin. A phase I-II study.

The combination of cisplatin (100 mg/m2) and 5-fluorouracil (5-FU) by continuous infusion (1 g/m2/day for 5 days) has been reported to produce a high response rate as neoadjuvant therapy for advanced squamous cell head and neck cancer. We sought to improve the response rate by increasing the dose of 5-FU to 1.5 g/m2/day and 2.

Plasma pharmacokinetics of cyclophosphamide and its cytotoxic metabolites after intravenous versus oral administration in a randomized, crossover trial.

Since cyclophosphamide is used by both oral and i.v. routes in the treatment of hematological and solid malignancies, we designed a randomized, crossover clinical trial to evaluate the pharmacokinetics of this anticancer agent after either administration route.