High-performance liquid chromatographic method for the determination of a novel thymidylate synthase inhibitor, AG 331, in human serum.

AG 331 is a novel thymidylate synthase inhibitor currently in Phase I clinical trial. To determine the pharmacokinetic parameters of AG 3331 in human subjects, a suitable analytical method was developed using high-performance liquid chromatography. Serum and urine samples were prepared using both solid-phase extraction and solvent extraction.

Paclitaxel 3-hour infusion given alone and combined with carboplatin: preliminary results of dose-escalation trials.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) by 3-hour infusion was combined with carboplatin in a phase I/II study directed to patients with non-small cell lung cancer. Carboplatin was given at a fixed target area under the concentration-time curve of 6.0 by the Calvert formula, whereas paclitaxel was escalated in patient cohorts from 150 mg/m2 (dose level I) to 175, 200, 225, and 250 mg/m2.

Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies.

Purpose: The purpose of our studies was to define the maximal-tolerated dose of liposomal doxorubicin (DOX-SL; Liposome Technology Inc, Menlo Park, CA), a doxorubicin formulation of polyethyleneglycol-coated liposomes, characterize the toxicities associated with this formulation, and evaluate any indication of antitumor activity within a phase I setting.

Patients And Methods: Two separate phase I studies were conducted following the initial human pharmacokinetic testing at one of the sites (Hadassah). The starting dose of 20 mg/m2 at the University of Southern California was just below the dose without toxicity in the pharmacokinetic study.

Phase II study of fluorouracil and its modulation in advanced colorectal cancer: a Southwest Oncology Group study.

Purpose: A variety of fluorinated pyrimidine-based regimens for the treatment of disseminated colorectal cancer have been presented in the medical literature. The Southwest Oncology Group designed a screening trial of seven regimens of fluorouracil (5-FU) to assess efficacy and toxicity afforded by biochemical modulation or schedule variations.

Patients And Methods: Six hundred twenty patients were entered into this trial between August 1989 and January 1993.

Phase I/II clinical and pharmacokinetic evaluation of liposomal daunorubicin.

Purpose: Since liposomal encapsulation of anticancer drugs may enhance antitumor activity while reducing toxicity in vitro, we evaluated liposomally encapsulated daunorubucin (DaunoXome; Vestar, Inc, San Dimas, CA) for safety, pharmacokinetics, and potential efficacy in patients with AIDS-related Kaposi's sarcoma (AIDS-KS).

Patients And Methods: Forty patients with advanced AIDS-KS were accrued. Successive cohorts received DaunoXome at doses of 10, 20, 30, and 40 mg/m2 given once every 3 weeks, and 40, 50, and 60 mg/m2 given once every 2 weeks.

A fixed-ratio combination of uracil and Ftorafur (UFT) with low dose leucovorin. An active oral regimen for advanced colorectal cancer.

Background: UFT is a fixed-ratio combination of uracil and Ftorafur, a prodrug that is absorbed orally and metabolized in vivo to 5-fluorouracil (5-FU). Uracil potentiates 5-FU through interference with its catabolism. The combination of UFT and leucovorin in patients with advanced incurable colorectal cancer, to evaluate preliminary activity and toxicity in this patient population.

Phase II clinical trial of carboplatin, ifosfamide, with oral mesna for metastatic breast carcinoma.

Twenty-five women with advanced breast carcinoma refractory to first-line chemotherapy entered a phase II trial to evaluate the efficacy of ifosfamide and carboplatin. Additionally the trial assessed the clinical usefulness of oral 2-mercaptoethane sulfonate (mesna) for urothelial protection. Two partial remissions were observed (8%); toxicity was significant but acceptable, with no treatment-related deaths.

Intraperitoneal 5-fluoro-2'-deoxyuridine (FUDR) and (S)-leucovorin for disease predominantly confined to the peritoneal cavity: a pharmacokinetic and toxicity study.

Intraperitoneal (IP) administration of fluorinated pyrimidines has been evaluated for ovarian and gastrointestinal malignancies in phase I, II, and III trials. The tolerance and pharmacokinetic profile of IP 5-fluoro-2'-deoxyuridine(FUDR) alone and with (R,S)-leucovorin ((R,S)-LV) have each been evaluated in previous phase I studies. FUDR doses of 3 g per day with and without (R,S)-LV doses up to 640 mg per day given IP are well tolerated.

Cytoprotection: concepts and challenges.

Clinical trials with several toxicity protectors (cytoprotective or chemoprotective agents) have been performed during the past decade. These trials are quite complex since they must include sufficient dose-limiting events for study, and assessment of both toxicity (and therefore the efficacy of protection) and antitumor effects must be carried out. However, it is inevitable that with greater understanding of drug actions, one seeks to manipulate these for greater antitumor activity (biochemical modulation) or for lesser dose-limiting toxicity (cytoprotection) or for both.

Paclitaxel (Taxol) in heavily pretreated ovarian cancer: antitumor activity and complications.

Objective: To analyze the efficacy and toxicity of Taxol in patients with ovarian cancer who had failed at least two previous chemotherapy treatment regimens.

Patients And Methods: Sixty-eight patients with advanced pretreated ovarian cancer, with either measurable or evaluable disease who were shown to have disease progression were entered on a National Cancer Institute sponsored 'compassionate' treatment referral center protocol and received intravenous infusion of Taxol over 24 hours 135 mg/m2, (after steroid-containing premedication) repeated every 3 weeks and continued while showing no evidence of progression.

Results: Of the 68 patients enrolled, 10 patients (15%) had a partial response and one assessable by marker only had improvement of disease.

Platinum compounds in cervical and endometrial cancers: focus on carboplatin.

Drug therapy for cervical cancer is slowly undergoing evaluation in early disease stages, in which it is more likely to make an impact. Cisplatin has been the principal drug used in systemic therapy for all stages, with the possible exception of the radiosensitizer hydroxyurea. Nevertheless, current studies use cisplatin in this role as well.

Platinum resistance. Experimental and clinical status.

It has become clear that multiple mechanisms of cellular resistance to platinum compounds exist; however, the knowledge that platinum resistance can not only be explained by processes such as reduced drug accumulation, and increased detoxification, has shifted the attention of researchers to more molecular mechanisms. The introduction of new techniques, such as the PCR technique for example, has opened the possibility to monitor genes involved in antitumor responses and may provide molecular information on the emergency of resistance.

Preclinical pharmacokinetics and stability of isophosphoramide mustard.

Stability and preclinical pharmacokinetics of isophosphoramide mustard (IPM), an active metabolite of ifosphamide, were investigated using analytical methods developed in this laboratory. For stability evaluation of IPM we used a rapid, high-pressure liquid chromatographic (HPLC) method by which IPM is analyzed directly from aqueous solutions without derivatization on a 10-microns C-18 reversed-phase column with theophylline as the internal standard. IPM in sodium phosphate buffers was found to undergo pH-dependent first-order degradations.

Teniposide: overview of its therapeutic potential in adult cancers.

Teniposide was introduced into clinical trials prior to etoposide, but its role was not defined because interest shifted early on to etoposide. However, long-term encouraging results obtained in acute leukemia treated with teniposide have rekindled interest in this compound. In addition to pharmacokinetic differences, teniposide has greater CNS penetrance and is more lipophilic.

Intraperitoneal 5-fluoro-2'-deoxyuridine with escalating doses of leucovorin: pharmacology and clinical tolerance.

In a preceding study, we established the tolerance and pharmacokinetic behavior of 5-fluoro-2'-deoxyuridine (FdUrd) given by the intraperitoneal (IP) route. A dose of 3 g daily x 3 days was found satisfactory for Phase II study and exploration of biochemical modulation. Therefore, the current study was conducted to study the tolerance and pharmacokinetics of such a dose-schedule and route of FdUrd combined with escalating doses of leucovorin (LV).

Phase I and pharmacologic study of liposomal daunorubicin (DaunoXome).

We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial dose-escalation steps from 10 to 60 mg/m2.

Drug-induced DNA modification in buccal cells of cancer patients receiving carboplatin and cisplatin combination chemotherapy, as determined by an immunocytochemical method: interindividual variation and correlation with disease response.

Twenty-six patients with a variety of tumor types were treated according to a phase 1 experimental treatment protocol consisting of repetitive cycles of cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II) (carboplatin, 200-480 mg/m2) at day 1 and cis-diamminedichloroplatinum(II) (cisplatin, 50-100 mg/m2) at day 3. Buccal cells were collected in one or two treatment cycles prior to carboplatin, 24 h after carboplatin, just prior to cisplatin, and approximately 24 h after cisplatin administration. Drug-induced DNA modification was visualized at the single cell level by anti-serum NKI-A59 and quantitated by microdensitometry.