Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer.

BACKGROUND: Preclinical studies in animal models have demonstrated tumor regression following intratumoral administration of an adenovirus vector containing wild-type p53 complementary DNA (Ad-p53). Therefore, in a phase I clinical trial, we administered Ad-p53 to 28 patients with non-small-cell lung cancer (NSCLC) whose cancers had progressed on conventional treatments. METHODS: Patients received up to six, monthly intratumoral injections of Ad-p53 by use of computed tomography-guided percutaneous fine-needle injection (23 patients) or bronchoscopy (five patients). The doses ranged from 10(6) plaque-forming units (PFU) to 10(11) PFU. RESULTS: Polymerase chain reaction (PCR) analysis showed the presence of adenovirus vector DNA in 18 (86%) of 21 patients with evaluable posttreatment biopsy specimens; vector-specific p53 messenger RNA was detected by means of reverse transcription-PCR analysis in 12 (46%) of 26 patients. Apoptosis (programmed cell death) was demonstrated by increased terminal deoxynucleotide transferase-mediated biotin uridine triphosphate nick-end labeling (TUNEL) staining in posttreatment biopsy specimens from 11 patients. Vector-related toxicity was minimal (National Cancer Institute's Common Toxicity Criteria: grade 3 = one patient; grade 4 = no patients) in 84 courses of treatment, despite repeated injections (up to six) in 23 patients. Therapeutic activity in 25 evaluable patients included partial responses in two patients (8%) and disease stabilization (range, 2-14 months) in 16 patients (64%); the remaining seven patients (28%) exhibited disease progression. CONCLUSIONS: Repeated intratumoral injections of Ad-p53 appear to be well tolerated, result in transgene expression of wild-type p53, and seem to mediate antitumor activity in a subset of patients with advanced NSCLC.

Pentoxifylline and ciprofloxacin in patients with myelodysplastic syndrome. A phase II trial.

Tumor necrosis factor (TNF) inhibits hematopoietic cell proliferation. The combination of pentoxifylline (PTX) and ciprofloxacin (Cipro) has been previously shown to reduce circulating serum levels of TNF. In this Phase II trial 14 patients with advanced myelodysplastic syndrome were treated with PTX (2,000 mg/day) and Cipro (1,000 mg/day) in order to determine tolerability and effect on peripheral blood cell counts, progenitor cell responsiveness to cytokines and circulating serum levels of interleukin-6 (IL6) and TNF. Toxicity attributed to PTX and Cipro were limited to nausea in 4 patients. Peripheral blood cell counts, platelet transfusion requirements and red blood cell transfusion requirements did not change during administration of PTX and Cipro (daily for 28 days). Marrow progenitor cells of patients entered into trial were less responsive to stimulation with cytokines in vitro at baseline and during the trial compared to normal volunteers. Eight patients had elevated IL6 levels before treatment with PTX and Cipro these levels did not change during therapy. Five patients had elevated TNF levels at baseline. There was a suggestion of decreased TNF levels during treatment with PTX and Cipro (P = .09). In conclusion, PTX and Cipro was well tolerated but no evidence of efficacy was observed.

Engraftment with peripheral blood stem cells using noncontrolled-rate cryopreservation: comparison with autologous bone marrow transplantation.

Peripheral blood stem cells (PBSC) are used increasingly as a source of stem cell support following myeloablative therapy. In this report, the results of 33 patients undergoing PBSC transplantation were compared to 17 concurrent patients undergoing autologous bone marrow transplantation (ABMT). PBSC were cryopreserved using 6% pentastarch and 5% dimethyl sulfoxide (DMSO) with noncontrolled-rate freezing. Many patients in the PBSC group were selected because they were excluded as candidates for ABMT due to prior pelvic irradiation, marrow tumor involvement, or other factors. PBSC were mobilized with high-dose cyclophosphamide (CY), CY+granulocyte-macrophage colony-stimulating factor (GM-CSF), or GM-CSF alone. Colony-stimulating factors were not administered after transplantation. A median of 7.4 x 10(8) mononuclear cells (MNC)/kg were collected containing a median of 3.2 x 10(4) granulocyte-macrophage colony-forming units (CFU-GM)/kg and 5.7 x 10(4) burst-forming units (BFU-E)/kg. After thawing, CFU-GM recovery was 67% and BFU-E recovery was 59%. The thawed, pooled PBSC contained 6.4 x 10(6) CD34+ cells/kg. The entire PBSC volume (median 870 mL) was infused over a median of 157 minutes. PBSC patients required a median of 15 days to achieve an ANC of 500/microL and 22 days for a platelet count of 50,000/microL. Neutrophil recovery was inversely correlated with the number of harvested progenitor cells (p = 0.014); the time to achieve a platelet count of 50,000/microL was inversely associated with CD34+ cells/kg (p = 0.005). PBSC transplant patients achieved an ANC of 500/microL 6 days faster (p < 0.05) and had a 10-day shorter hospitalization (p < 0.05) than ABMT patients. Use of noncontrolled-rate cryopreserved PBSC is associated with faster engraftment and shorter hospital duration than ABMT.

Hematopoietic growth factors after allogeneic marrow transplantation in animal studies and clinical trials.

The use of hematopoietic growth factors after allogeneic bone marrow transplantation (BMT) was investigated either in a preclinical canine model or in patients. G-CSF administration in dogs after high-dose total body irradiation (TBI) and transplantation of DLA-identical littermate marrow significantly accelerated recovery of peripheral blood neutrophils, monocytes and lymphocytes, but not of platelet counts, without significantly increasing the risks of graft failure or graft-versus-host disease (GVHD). GM-CSF given to patients after HLA-identical sibling BMT was well tolerated at doses < or = 250 micrograms/m2/day and resulted in significantly faster neutrophil recovery compared with matched historical controls. Risks of graft failure, GVHD or relapse were not increased. When GM-CSF was given after matched or 1-antigen mismatched unrelated BMTs, the number of febrile days and septic episodes within the first 28 days was reduced even though neutrophil recovery was not accelerated. Incidences of graft failure, GVHD or relapse were not increased. In recipients of BMT with invasive fungal infections, M-CSF in combination with conventional anti-fungal therapy may have a beneficial effect on survival. Treatment with GM-CSF in patients with graft failure appears to result in improved survival without increasing the risks of GVHD or relapse.