Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors.

PURPOSE: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy. PATIENTS AND METHODS: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses). RESULTS: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and 1,250/500 mg/m(2) for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA. CONCLUSION: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m(2).

A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity.

Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first FT inhibitors to undergo clinical testing. We report a Phase I trial to assess the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid tumors received 92 courses of escalating SCH66336 doses given orally twice a day (b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336 b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation in buccal mucosa cells of patients treated with SCH66336 was demonstrated, confirming that SCH66336 inhibits protein farnesylation in vivo. One partial response was observed in a patient with previously treated metastatic non-small cell lung cancer, who remained on study for 14 months. This study not only establishes the dose for future testing on this schedule (350 mg b.i.d.) but also provides the first evidence of successful inhibition of FT in the clinical setting and the first hint of clinical activity for this class of agents.

Phase I and pharmacokinetic study of irinotecan and docetaxel in patients with advanced solid tumors: preliminary evidence of clinical activity.

PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m(2), 160/65 mg/m(2), 200/65 mg/m(2), and 200/75 mg/m(2)) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non-small-cell lung cancer, achieved partial remissions. CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m(2) and docetaxel 65 mg/m(2).

History of the development of antiemetic guidelines at Mayo Clinic Rochester.

This article describes the historic experience of the development of antiemetic guidelines for patients taking chemotherapy drugs at Mayo Clinic Rochester. The initial guidelines for the use of serotonin (5-hydroxytryptamine3) receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting were developed in early 1995 and implemented in September 1995. In February 1997, the guidelines were reviewed and modified. In the spring of 1998, major changes were made based on new data from the literature and discussions with antiemetic authorities in the United States. These guidelines were implemented in July 1998. The guidelines were again reviewed and modified in December 1998. In addition, we compared costs associated with the 1997 guidelines and the December 1998 guidelines. The developed guidelines, utilizing clinically available agents, seem to provide high-quality patient care at a reasonable cost.

Self-assembly of DNA-polymer complexes using template polymerization.

The self-assembly of supramolecular complexes of nucleic acids and polymers is of relevance to several biological processes including viral and chromatin formation as well as gene therapy vector design. We now show that template polymerization facilitates condensation of DNA into particles that are <150 nm in diameter. Inclusion of a poly(ethylene glycol)-containing monomer prevents aggregation of these particles. The DNA within the particles remains biologically active and can express foreign genes in cells. The formation or breakage of covalent bonds has until now not been employed to compact DNA into artificial particles.

Experimental evaluation of expanded polytetrafluoroethylene for reconstruction of orbital floor defects.

OBJECTIVE: This study evaluates the efficacy of a medical grade expanded polytetrafluoroethylene (e-PTFE) sheet for reconstruction of the orbital floor. MATERIALS AND METHODS: Orbital floor defects were created in 10 domestic sheep and reconstructed with the 1-mm thick e-PTFE sheet. The surgical sites were evaluated for the development of enophthalmos and biocompatibility at 2 weeks, and at 1-, 2-, 4-, and 6-months intervals. RESULTS: The results of this indicate that the e-PTFE material has excellent handling characteristics, provides stability to correct surgically created enophthalmos, and causes essentially no foreign body reaction. CONCLUSION: Expanded polytetrafluoroethylene proved to be an excellent alloplastic material for the repair of orbital floor defects in this experimental study.

Maxillary and mandibular reconstruction using calvarial bone grafts and Branemark implants: a preliminary report.

A review of 24 patients reconstructed with calvarial bone grafts and 93 Branemark implants (Nobelpharma, Chicago, IL) revealed an overall success rate of 91.4%. Two grafting techniques were used. A vertical grafting technique with delayed implant placement had an 86% success rate in 13 patients who had 50 implants placed. The average follow-up for this group was 31 months. A horizontal grafting technique with immediate implant placement had a success rate of 98%. This group included 13 patients who had 43 implants placed at the time of their bone grafting procedure. Two patients had a combination of grafting techniques. The average follow-up for this group was 18 months. A patient questionnaire revealed a high percentage and degree of satisfaction.

Autologous calvarial and iliac onlay bone grafts in miniature swine.

Calvarial bone has been reported to be superior to iliac bone for onlay bone grafting due to decreased resorption. This study evaluated the physical, histologic, and radiographic characteristics of calvarial and corticocancellous iliac onlay bone grafts in nine Pitman-Moore miniature swine at 2 weeks, and at 1-, 2-, 4-, 6-, 7-, 8-, 10-, and 12-month intervals. Compared with iliac grafts, the calvarial onlay grafts had more than a twofold greater radiographic density. Statistical analysis of the mature grafts using the standard of estimated means of the bone graft volumes revealed 85% retention of the calvarial grafts compared with 34% retention of the grafted iliac bone. There was no subjective difference in the rate or degree of revascularization between the two grafted materials.

Effect of sulfadimethoxine-ormetoprim in the treatment of calves with induced Pasteurella pneumonia.

The efficacy of sulfadimethoxine (SDM)-ormetoprim (OMP) was evaluated in calves with induced Pasteurella pneumonia. A dose-titration study comparing 3 doses of SDM-OMP was performed to determine the optimal dose. Treatments included: group 1--nontreated controls; group 2--33 mg of SDM-OMP/kg of body weight, orally on day 1 and 17 mg/kg on days 2 to 5; group 3--66 mg of SDM-OMP/kg, orally on day 1 and 33 mg/kg on days 2 to 5; group 4--99 mg of SDM-OMP/kg, orally on day 1 and 50 mg/kg on days 2 to 5; and group 5--11 mg of oxytetracycline/kg, IV daily for 4 days. Group-2 calves responded to treatment as well as did group-5 calves. Group-4 calves responded the same as did group-3 calves. However, group-2 calves did not respond as well as did groups 3, 4, and 5 calves.

Toxic effects of lasalocid in horses.

Lasalocid was given to horses in a series of sequentially increasing single oral doses ranging between 5 and 30 mg/kg of body weight, with an appropriate washout period between treatments. One of the 5 horses died after a dosage of 15 mg/kg, 1 of 3 horses died after 21 mg/kg, 1 of 3 horses died after 22 mg/kg, and 1 of 2 horses died after 26 mg/kg. The LD50 of lasalocid for horses was estimated to be 21.5 mg/kg. Monensin was given to horses in a similar manner at dosages of 1, 2, and 3 mg/kg of body weight. One of the 2 horses died after a dosage of 2 mg/kg and 1 horse died after a dosage of 3 mg/kg. The clinical signs of toxicosis observed in horses given either drug were progressive and included depression, ataxia, paresis, and paralysis with partial anorexia. Intermittent profuse sweating was observed before death in horses given monensin.

Pharmacokinetics of sulphadimethoxine in cattle.

Four healthy Angus steers received a single rapid intravenous injection of sulphadimethoxine at a dose of approximately 55 mg/kg. The elimination half-life determined from plasma concentration-time data was approximately 12-5 h, and the volume of distribution was 31-0 per cent of body weight. Animals also received sulphadimethoxine intravenously or orally at a loading dose of approximately 55 mg/kg, followed by sustaining oral doses of approximately 27-5 mg/kg at 24, 48 and 72 h. It was demonstrated that oral maintenance doses served to sustain sulphonamide plasma concentrations achieved with the loading dose.