Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require a vascular approach to broadly ...transduce muscle cells. We tested the impact of preexisting AAV antibodies on microdystrophin expression following vascular delivery to nonhuman primates. Rhesus macaques were treated by isolated limb perfusion using a fluoroscopically guided catheter. In addition to serostatus stratification, the animals were placed into one of the three immune suppression groups: no immune suppression, prednisone, and triple immune suppression (prednisone, tacrolimus, and mycophenolate mofetil). The animals were analyzed for transgene expression at 3 or 6 months. Microdystrophin expression was visualized in AAV, rhesus serotype 74 sero-negative animals (mean: 48.0 ± 20.8%) that was attenuated in sero-positive animals (19.6 ± 18.7%). Immunosuppression did not affect transgene expression. Importantly, removal of AAV binding antibodies by plasmapheresis in AAV sero-positive animals resulted in high-level transduction (60.8 ± 18.0%), which is comparable with that of AAV sero-negative animals (53.7 ± 7.6%), whereas non-pheresed sero-positive animals demonstrated significantly lower transduction levels (10.1 ± 6.0%). These data support the hypothesis that removal of AAV binding antibodies by plasmapheresis permits successful and sustained gene transfer in the presence of preexisting immunity (natural infection) to AAV.
A total of 120 episodes of infection in 113 cancer patients were treated with intravenous trimethoprim-sulfamethoxazole (TMP-SMX) alone (92 episodes) or with TMP-SMX plus continuous infusion ...tobramycin (28 episodes). The overall response rates were 47% and 75%, respectively. The majority of episodes had failed to respond to prior antibiotics. Pneumonia was the most common infection, and Klebsiella pneumoniae was the most common pathogen. TMP-SMX plus tobramycin cured 86% of episodes of septicemia and 76% of episodes of pneumonia, whereas TMP-SMX alone cured 20% and 42%, respectively. The initial neutrophil count did not appear critical in determining the outcome of infection. It was the change in the neutrophil count during the infection that appeared important. The outcome of infection was less favorable where abnormal renal and/or hepatic functions were documented. The sensitivity of the organism in vitro to TMP-SMX and/or tobramycin correlated well with the in vivo response. Intravenous TMP-SMX was well tolerated with a 4% incidence of reversible toxicity. A 15% incidence of renal toxicity was attributable to tobramycin. Intravenous TMP-SMX appears to be useful antimicrobial regimen for the therapy of infections caused by susceptible organisms in cancer patients.
Comparative studies of cefamandole and cephalothin were carried out in 32 cancer patients. After rapid intravenous injection of 1 gm cefamandole or cephalothin, the peak mean serum concentrations in ...11 patients achieved at 0.25 hr were 103.4 mcg/ml and 56.7 mcg/ml, respectively. Except at 6 hr, the serum concentration of cefamandole was higher (p < 0.05) at alt times. The terminal half‐lives (t½) were similar, being 1.2 hr for cefamandole and 1.0 hr for cephalothin. Cefamandole, 1 gm intramuscularly, induced a peak mean serum concentration of 26.6 mcg/ml at 1 hr, with a slow decay. Intermittent cefamandole (2 gm intravenously every 6 hr) induced very high mean serum concentrations (7 patients), but at 4 hr the concentrations were similar to those after 1 gm intravenously. Per cent of urinary excretion was simi lar for both drugs regardless of dose and mode of administration. Continuous‐infusion cefamandole or cephalothin (2 gm loading followed by 2 gm every 6 hr) in 14 patients showed consistently higher serum concentrations for cefamandole (p < 0.05) over a 5‐day period. There was no evidence of drug accumulation in the multiple‐dose studies. Both the single‐ and multiple‐dose schedules were well tolerated.
Trimethoprim-sulfamethoxazole (TMP-SMZ) was used alone and in combination with other antimicrobial agents as treatment for infections in patients with cancer. Patients who did not respond to previous ...treatment with combinations of antibiotics received TMP-SMZ orally or parenterally during a total of 127 episodes of infection. The combined response rate for these two routes of administration was 49%, and the individual rates were similar for both routes. Twenty-eight infections were treated with TMP-SMZ plus tobramycin, and 75% responded after treatment with other drugs had failed. Ticarcillin plus TMP-SMZ was used as initial therapy for presumed or proved infection during 276 episodes of fever. Of 102 documented infections, 77% responded. Toxicity from TMP-SMZ was minimal.
One hundred eligible patients with inoperable, locally advanced or metastatic squamous cell carcinoma of the head and neck region following prior therapy were randomized to receive im methotrexate ...(50 patients) or iv cisplatin (50 patients). Methotrexate produced a complete plus partial response rate of 16.0% and cisplatin produced a partial response rate of 8.0%, with median durations of response of 18 and 8 weeks, respectively. The corresponding median survival times were 20 and 18 weeks. Methotrexate responders survived 60 weeks, versus 17 weeks for nonresponders. The corresponding survival times for cisplatin-treated patients were 38 and 18 weeks. Good pretreatment performance status had a significantly positive effect on survival (P = 0.04), but prior therapy did not. Toxicity secondary to either agent occurred with the expected frequency. The two agents examined showed comparable antitumor activity in patients with squamous cell carcinoma of the head and neck who had not previously received chemotherapy.
Peptichemio is a peptide complex of m-L-phenylalanine mustard. A clinical evaluation of this agent was conducted in 116 patients, of whom 104 were evaluable for both toxicity and response. The ...majority of patients had solid tumors. The drug was administered iv daily for 3 days at doses of 20-75 mg/m2/day, with courses repeated at 3-4-week intervals. The optimal dose schedule appears to be 45 mg/m2/day for 3 days. The major side effects were cumulative myelotoxicity, phlebitis, and mild nausea and vomiting. No other major organ toxicity was observed. The partial remission rate was 7%. Most patients had received an alkylating agent as part of their previous therapy. There were seven partial responses and four less than partial responses achieved in patients with melanoma, lymphoma, and gastrointestinal, genitourinary, breast, and head and neck carcinomas. Responses lasted 4-36 weeks.
Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF ...signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.
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