Clin Cancer Res
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Comparative Study
Comparative study of the antitumor activity of free doxorubicin and polyethylene glycol-coated liposomal doxorubicin in a mouse lymphoma model.
Here, we investigate various factors affecting the therapeutic efficacy of free doxorubicin (Free-Dox) and polyethylene glycol (PEG)-coated (PEGylated) liposomal doxorubicin (referred to as Doxil) in the ascitic J6456 lymphoma model of BALB/c mice. Free drug and liposomal drug were affected differently by the tumor burden and route of treatment administration. A delay in start of treatment from day 1 to day 5 almost completely abolished the efficacy of Free-Dox, whereas that of Doxil was only minimally reduced. ⋯ Overall, Doxil given by the systemic i.v. route was the most effective treatment in prolonging median survival and obtaining cures. Variations in the dose-schedule treatment regime confirm the superior therapeutic profile and reduced dependence on tumor burden of the PEGylated liposomal formulation over free drug. In addition, these experiments indicate that, at equal dose intensity, the dose level is more important than the frequency of administration for therapeutic activity.
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Clinical Trial
Factors affecting mobilization of peripheral blood progenitor cells in patients with lymphoma.
The objective of this study was to identify factors associated with poor mobilization of peripheral blood progenitor cells (PBPCs) or delayed platelet engraftment after high-dose therapy and autologous stem cell transplantation in patients with lymphoma. Fifty-eight patients with Hodgkin's disease or non-Hodgkin's lymphoma underwent PBPC transplantation as the "best available therapy" at Memorial Sloan-Kettering Cancer Center (New York, NY) between 1993 and 1995. PBPCs were mobilized with either granulocyte colony-stimulating factor (G-CSF) alone (n = 19) or G-CSF following combination chemotherapy (n = 39). ⋯ Patients who received > or = 11 cycles of chemotherapy prior to PBPC mobilization tended to have delayed platelet recovery to > 20,000/microliter and to require more platelet transfusions than less extensively pretreated patients (median, 13.5 versus 23.5 days; P = 0.15; median number of platelet transfusion episodes, 13 versus 9; P = 0.17). These data suggest that current strategies to mobilize PBPCs may be suboptimal in patients who have received either stem cell-toxic chemotherapy or > or = 11 cycles of chemotherapy prior to PBPC mobilization. Alternative approaches, such as ex vivo expansion or the use of other growth factors in addition to G-CSF, may improve mobilization of progenitor cells for PBPC transplantation.
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The camptothecins are a class of potent cytotoxic anticancer agents that interact with the nuclear enzyme topoisomerase I to produce lethal DNA strand cleavages. 9-Amino-20(S)-camptothecin (9AC) was introduced into Phase I clinical trials in dimethylacetamide and polyethylene glycol 400 in a 10 mM phosphoric acid vehicle for i.v. solubility. A lyophilized colloidal dispersion (CD) of 9AC for reconstitution with 20% dextrose in normal saline was developed as an alternative formulation. Patients (ages 25-75 years) with normal liver and kidney function, Eastern Cooperative Oncology Group performance status < or = 2, and up to two prior chemotherapy regimens were treated. ⋯ Although no objective responses were seen, 9 of 25 patients exhibited stable disease for 2-6 months. The plasma pharmacokinetics of 9AC lactone in cancer patients were comparable between the 9AC CD and soluble formulations. The dosing regimen recommended for Phase II trials of the 9AC CD formulation is 54.2 micrograms/m2/h, given as a 72-h continuous i.v. infusion every 3 weeks.
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Fotemustine is a chloroethylnitrosourea with antitumor activity in disseminated melanoma and adult primary brain tumors. Because new drugs are required for the treatment of medulloblastoma in children, we evaluated the preclinical antitumor activity of fotemustine in four s.c. medulloblastoma xenografts, in comparison with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Both drugs were administered as a single i.p. injection to nude mice bearing advanced-stage tumor. ⋯ The high in vivo sensitivity to fotemustine and BCNU observed in three xenografts was clearly associated with a low ATase activity (> 20 fmol/mg), whereas the two poorly sensitive or refractory medulloblastoma xenografts showed high ATase activity (> 500 fmol/mg). Alkylpurine-DNA N-glycosylase activity was detected in all tumor xenografts but at levels ranging only from 513 to 1105 fmol/mg/h; no consistent relationship was found between alkylpurine-DNA N-glycosylase activity and the in vivo sensitivity to the two chloroethylnitrosoureas. The improved activity and tolerance of fotemustine in comparison with BCNU in pediatric medulloblastoma xenografts strongly support the clinical development of this agent in children with brain tumors, in which ATase should be examined as a potential prognostic indicator.
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Multicenter Study Clinical Trial Controlled Clinical Trial
Phase I trial of orally administered pentosan polysulfate in patients with advanced cancer.
Tumor angiogenesis is critically important to tumor growth and metastasis. We have shown that pentosan polysulfate (PPS) is an effective inhibitor of heparin-binding growth factors in vitro and can effectively inhibit the establishment and growth of tumors in nude mice. Following completion of our Phase I trial of s.c. administered PPS, we performed a Phase I trial of p.o. administered PPS in patients with advanced cancer to determine the maximum tolerated dose (MTD) and toxicity profile and to search for any evidence for biological activity in vivo. ⋯ The tested doses and schedule cannot be recommended for further study. Subsequent murine experiments showed PPS to be more effective as an anticancer agent when it is given intermittently. We propose a study of PPS given on a weekly schedule in further clinical trials.