cgp-48664 and Neoplasm-Metastasis

To determine the activity and tolerability of SAM496A, an inhibitor of S-adenosylmethionine decarboxylase (SAMDC), in patients with metastatic melanoma who had not received prior chemotherapy. Selected patients were offered participation in two sub-studies examining early changes in tumor metabolism with FDG-PET and changes in tumor polyamine content.. Fifteen patients with measurable metastatic melanoma, normal cardiac function, and no known CNS metastases were eligible and received SAM486A by 1-hour IV infusion daily for 5 days every 3 weeks. Response was assessed by SWOG criteria.. No patient had a confirmed partial response. Fatigue/lethargy, myalgia and neutropenia were the main toxicities but no febrile neutropenia or grade 4 non-hematological toxicity occurred. Five patients had PET scans pre-treatment and on days 8-12 of cycle 1. No patient had reduction of tumor metabolism. Serial biopsy in one patient showed alterations in polyamines consistent with SAMDC inhibition.. Using the present dose and schedule of administration, SAM486A does not have significant therapeutic potential in patients with metastatic melanoma.

Topics: Adenosylmethionine Decarboxylase; Adult; Aged; Amidines; Antineoplastic Agents; Female; Fluorodeoxyglucose F18; Humans; Indans; Karnofsky Performance Status; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Positron-Emission Tomography; Radiopharmaceuticals

The purpose of our study was to determine the maximum-tolerated dose, dose-limiting toxicity, safety profile, and pharmacokinetics of the polyamine synthesis inhibitor SAM486A given in combination with 5-fluorouracil/leucovorin (5-FU/LV) in cancer patients.. Patients with advanced colorectal cancer were treated with 5-FU [bolus (400 mg/m(2)) followed by a 22-h infusion (600 mg/m(2))] and LV (200 mg/m(2)) and escalating doses of SAM486A, 1-3-h infusion daily for 3 days. Plasma sampling was performed to characterize the pharmacokinetics and pharmacodynamics of the combination. Twenty-seven patients with metastatic colorectal cancer and 1 with pseudomyxoma peritonei were treated. Twenty-six patients received SAM486A in the combination at doses ranging from 25 to 150 mg/m(2)/day. Dose-limiting toxicity consisting of fatigue grade 3 was seen at 150 mg/m(2)/day. Other adverse events included neutropenia, hand and foot syndrome, nausea, vomiting, diarrhea, and constipation. Fifteen of 26 patients evaluable for best response according to the Southwest Oncology Group criteria achieved a partial response [8 (30%) of 26] or stable disease [9 (35%) of 26]. SAM486A did not influence the pharmacokinetics of 5-FU, and SAM486A clearance was similar to that when used as a single agent.. The novel molecular agent SAM486A is tolerable and safe in combination with a standard 5-FU regimen in patients with advanced colorectal cancer. The dose of SAM486A recommended for additional studies with this combination is 125 mg/m(2)/day. A disease-directed evaluation of SAM486A using this regimen is warranted.

Topics: Adult; Aged; Amidines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Colorectal Neoplasms; Female; Fluorouracil; Humans; Indans; Infusions, Intravenous; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pseudomyxoma Peritonei; Rectal Neoplasms; Treatment Outcome

We have previously reported that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces pulmonary metastasis from MDA-MB-435 human breast cancer xenografts without affecting the volume of the primary tumors (Manni et al. Clin Exp Mets 20:321, 2003). In these experiments, we show that DFMO treatment (2% in drinking H(2)O) reduced the growth fraction of the primary tumors by 60%. However, this effect was counter-balanced by a similar reduction in non-apoptotic necrosis, thus accounting for the preservation of tumor volume in DFMO-treated mice. DFMO treatment caused a 4-fold increase in cytoplasmic staining for cleaved caspase-3 (as opposed to the nuclear staining observed in control tonsil tissue) in the absence of histologic evidence of apoptosis. DFMO treatment reduced the number of mice with pulmonary metastasis by approximately 80% and the number of metastasis per mouse by >90% in association with a reduction in invasiveness of the primary tumor in the surrounding dermis and muscle by approximately 30%. DFMO treatment increased ERK phosphorylation in the tumors, an effect that has been found by us in vitro to be causally linked to the anti-invasive effect of the drug (Manni et al. Clin Exp Metast 2004; 21: 461]. DFMO also increased tyrosine phosphorylation of STAT-3 and expression of STAT-1 and JNK proteins. Administration of SAM486A (1 mg/kg/i.p. daily), an inhibitor of S-adenosylmethionine decarboxylase, either individually or in combination with DFMO, was not found to exert any biological or biochemical effects, most likely as a result of its failure to suppress tissue polyamine levels under these experimental conditions.

Topics: Amidines; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Death; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Eflornithine; Female; Humans; Indans; JNK Mitogen-Activated Protein Kinases; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Polyamines; STAT1 Transcription Factor; STAT3 Transcription Factor