PubMed · 8999717
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H Kühnle. 1996. [Taxol].. https://pubmed.ncbi.nlm.nih.gov/8999717/
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BACKGROUND: Diffuse pontine gliomas remain one of the most lethal of pediatric malignancies despite the use of increasingly intensive therapies. We delivered intensive chemotherapy during and following 70.2 Gy of hyperfractionated radiation therapy in an attempt to improve survival. PROCEDURE: Nine consecutive children with diffuse pontine gliomas were treated on this single arm study. Carboplatin, given in combination with fixed dose etoposide, was escalated in successive cohorts to determine its maximum tolerated systemic exposure (AUC). Outcome was coded based on imaging characteristics and clinical status. RESULTS: Eight of the nine children on this study died of their disease at a median of 44 weeks, essentially the same survival as those treated on a previous Pediatric Oncology Group study using hyperfractionated radiation therapy alone. Toxicity was almost exclusively hematologic and not associated with significant morbidity. CONCLUSIONS: The use of concurrent carboplatin and etoposide with hyperfractionated radiation therapy did not appear to improve the survival in this group of children with diffuse pontine gliomas. The toxicity of this chemotherapy during radiation therapy was primarily hematologic and well tolerated. New approaches to the treatment of these tumors need to be investigated.
PURPOSE: The addition of chemotherapy to radical radiotherapy (XRT) has been shown to improve survival in locally advanced nonsmall cell lung cancer (9). Consequently, different chemotherapeutic regimens in combination with XRT are being evaluated in the treatment of this disease. Paclitaxel (TAXOL) may be a valuable drug in this situation as, in addition to a demonstrated activity in NSCLC, it has been shown to enhance the effect of radiation on cell lines in vitro. METHODS AND MATERIALS: Seventeen patients were enrolled onto a Phase I/II trial to determine the maximum tolerated dose of paclitaxel given by a 3-h infusion every 2 weeks throughout a 6-week course of XRT, 60 Gy in 30 daily fractions, in patients with Stage III NSCLC and then to describe the response rate of this combination in an expanded cohort of patients treated at the recommended phase II dose. Three patients were entered at each dose level (45, 90, 120, and 135 mg/m2), except for the 120 mg/m2 dose level, which was expanded to nine patients. RESULTS: The dose limiting toxicity was neutropenia--two of three patients treated at the 135 mg/m2 level experienced Grade 3 neutropenia on day 15, which precluded administration of scheduled chemotherapy. Esophagitis was mild to moderate, and although profound lymphopenia was observed at all dose levels, there was no evidence of associated opportunistic infections. Of the nine patients treated at the recommended Phase II dose of 120 mg/m2, there were one complete and six partial responses (response rate 78%). CONCLUSION: The combination of XRT, 60 Gy in 6 weeks and paclitaxel, 120 mg/m2 q 2 weeks, can be safely given to patients with NSCLC, and although it demonstrates activity in this situation, consideration should be given to the addition of other agents, such as platinum compounds.
The inhibitor of apoptosis (IAP) family of proteins are highly conserved through evolution. However, the mechanisms by which these proteins interfere with apoptotic cell death have been enigmatic. Recently, we showed that one of the human IAP family proteins, XIAP, can bind to and potently inhibit specific cell death proteases (caspases) that function in the distal portions of the proteolytic cascades involved in apoptosis. In this study, we investigated three of the other known members of the human IAP family, c-IAP-1, c-IAP-2 and NAIP. Similarly to XIAP, in vitro binding experiments indicated that c-IAP-1 and c-IAP-2 bound specifically to the terminal effector cell death proteases, caspases-3 and -7, but not to the proximal protease caspase-8, caspases-1 or -6. In contrast, NAIP failed to bind tightly to any of these proteases. Recombinant c-IAP-1 and c-IAP-2 also inhibited the activity of caspases-3 and -7 in vitro, with estimated Kis of <=0.1 microM, whereas NAIP did not. The BIR domain-containing region of c-IAP-1 and c-IAP-2 was sufficient for inhibition of these caspases, though proteins that retained the RING domain were somewhat more potent. Utilizing a cell-free system in which caspases were activated in cytosolic extracts by addition of cytochrome c, c-IAP-1 and c-IAP-2 inhibited both the generation of caspase activities and proteolytic processing of pro-caspase-3. Similar results were obtained in intact cells when c-IAP-1 and c-IAP-2 were overexpressed by gene transfection, and apoptosis was induced by the anticancer drug, etoposide. Cleavage of c-IAP-1 or c-IAP-2 was not observed when interacting with the caspases, implying a different mechanism from the baculovirus p35 protein, the broad spectrum suicide inactivator of caspases. Taken together, these findings suggest that c-IAP-1 and c-IAP-2 function similarly to XIAP by inhibiting the distal cell death proteases, caspases-3 and -7, whereas NAIP presumably inhibits apoptosis via other targets.