Lymphomatoid granulomatosis following autologous stem cell transplantation.
(9/20433)
Lymphomatoid granulomatosis (LYG) is a rare angio-destructive lymphoproliferative disorder (LPD) of uncertain etiology, with prominent pulmonary involvement. Recent studies indicate that LYG is an Epstein-Barr virus (EBV)-associated B cell LPD with large numbers of background reactive T lymphocytes (T cell-rich B cell lymphoma). Although the disease frequently, but not exclusively, occurs in various immunodeficiency states, it has not been reported in association with the transient immunosuppression following autologous bone marrow/peripheral stem cell transplantation (ABM/PSCT). We describe a patient who developed lymphomatoid granulomatosis of the lung approximately 2 weeks after high-dose chemotherapy and autologous peripheral stem cell transplantation for multiple myeloma. Although molecular studies showed no evidence of EBV genome in the biopsy material, the serologic profile with high IgM titers was suggestive of primary EBV infection. Complete radiologic remission occurred following reconstitution of the patient's immune response after a 2-week course of ganciclovir treatment. Despite the apparently low frequency of LPD (both LYG and EBV-associated post-transplant lymphoma) in the ABMT setting, we believe that it should be considered in the differential diagnosis of patients whose clinical course following ABMT is complicated by fevers, in the absence of an identifiable infectious process. (+info)
Phase I study of escalating doses of edatrexate in combination with paclitaxel in patients with metastatic breast cancer.
(10/20433)
Motivated by the observation of preclinical synergy, a Phase I dose escalation study of edatrexate in combination with a 3-h paclitaxel infusion was performed in patients with advanced breast cancer to determine the maximum tolerated dose (MTD) of edatrexate and the toxicities associated with this combination and to report preliminary observations of efficacy with this novel combination. Thirty-six patients were enrolled in this Phase I trial. Thirty-five eligible patients were treated every 21 days in cohorts of at least three patients and were assessable for toxicity. One patient was ineligible due to hyperbilirubinemia. Stepwise dose escalations of edatrexate were administered until grade >3 nonhematological dose-limiting toxicities were reported. The initial dose level of edatrexate was 180 mg/m2; subsequent cohorts were treated with escalating doses of edatrexate (210, 240, 270, 300, 350, and 400 mg/m2). Edatrexate was administered by i.v. infusion over 1 h. Paclitaxel was administered 24 h later at a fixed dose of 175 mg/m2 as a 3-h infusion with standard dexamethasone, diphenhydramine, and cimetidine premedication. The MTD of edatrexate was reached at the 350 mg/m2 level in this study. Grade 3 diarrhea was seen in one patient at the 300 and 400 mg/m2 dose levels, requiring dose reductions. Two patients experienced grade 4 stomatitis at the 400 mg/m2 dose level and also required dose reduction, establishing the MTD as 350 mg/m2. Grade 3 nausea and vomiting were noted in two of three patients at the highest dose level. Of 35 patients, 4 patients reported grade 3 myalgias and 1 patient reported grade 3 neurosensory complaints, which were seen mostly at the 350 and 400 mg/m2 dose levels; however, 1 patient reported grade 3 myalgias at 180 mg/m2. No cumulative neurotoxicity was observed, and no patient experienced an allergic reaction to paclitaxel. In 23 patients with bidimensionally measurable disease, there were four complete (17%) and seven partial responses, with an overall response rate of 48% (95% confidence interval, 27-69%). All of the responses were seen in patients who had not received prior chemotherapy for stage IV disease. The median duration of response was not assessable because many responding patients went on to receive high-dose chemotherapy treatment with stem cell support. The combination of edatrexate and paclitaxel for treatment of metastatic breast cancer is a feasible and safe regimen. The MTD of edatrexate was 350 mg/m2 when combined with a 3-h infusion of paclitaxel (175 mg/m2) given 24 h later. Activity was noted even among patients who had relapsed shortly after receiving methotrexate- and/or doxorubicin-containing adjuvant regimens. Additional studies evaluating the sequences and dosing schema for this combination are warranted to improve the response proportion and define the duration of the response. (+info)
Phase I study of eniluracil, a dihydropyrimidine dehydrogenase inactivator, and oral 5-fluorouracil with radiation therapy in patients with recurrent or advanced head and neck cancer.
(11/20433)
5-Fluorouracil (5-FU) is an effective enhancer of radiation therapy (RT) in head and neck cancers. Due to rapid, predominantly hepatic metabolism by dihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from prolonged drug exposure, 5-FU is commonly given by continuous infusion. Eniluracil is a novel DPD-inactivator designed to prolong the half-life of 5-FU and provide sustained plasma concentrations of 5-FU with oral dosing. We conducted a Phase I study of the safety and efficacy of eniluracil given with oral 5-FU in patients receiving concurrent RT for recurrent or advanced squamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or high-risk (defined as an expected 2-year survival rate of <10%) head and neck cancer were enrolled and treated with concomitant chemoradiotherapy on an every-other-week schedule. Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 consecutive days (days 1-7). 5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The remaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of 5-FU was 2.5 mg/m2 given BID. Dose escalation in patient cohorts was scheduled at 2.5-mg/m2 increments, with intrapatient dose escalation permitted. Lymphocyte DPD activity and serum 5-FU and uracil concentrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patients. Sustained, presumed therapeutic concentrations of 5-FU were observed at a dose of 5.0 mg/m2 given BID. Cumulative dose-limiting myelosuppression (both neutropenia and thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m2 5-FU BID. One patient died of neutropenic sepsis during cycle 4. Other late cycle toxicities included diarrhea, fatigue, and mucositis. Grade 3 mucositis was observed in 4 patients, but no grade 4 mucositis or grade 3 or 4 dermatitis was observed. A second patient death occurred during cycle 1 of treatment. No specific cause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of oral 5-FU given with the DPD-inactivator eniluracil on an every-other-week schedule. Clinical radiation sensitization was not observed, based on the absence of dose-limiting mucositis and dermatitis. Alternative dosing schedules need to be examined to determine the most appropriate use of eniluracil and 5-FU as radiation enhancers. (+info)
A phase I and pharmacokinetic study of losoxantrone and paclitaxel in patients with advanced solid tumors.
(12/20433)
A Phase I and pharmacological study was performed to evaluate the feasibility, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetics of the anthrapyrazole losoxantrone in combination with paclitaxel in adult patients with advanced solid malignancies. Losoxantrone was administered as a 10-min infusion in combination with paclitaxel on either a 24- or 3-h schedule. The starting dose level was 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel (as a 24- or 3-h i.v. infusion) without granulocyte colony-stimulating factor (G-CSF). Administration of these agents at the starting dose level and dose escalation was feasible only with G-CSF support. The following dose levels (losoxantrone/paclitaxel, in mg/m2) of losoxantrone and paclitaxel as a 3-h infusion were also evaluated: 50/135, 50/175, 50/200, 50/225, and 60/225. The sequence-dependent toxicological and pharmacological effects of losoxantrone and paclitaxel on the 24- and 3-h schedules of paclitaxel were also assessed. The MTD was defined as the dose at which >50% of the patients experienced DLT during the first two courses of therapy. DLTs, mainly myelosuppression, occurring during the first course of therapy were noted in four of six and five of eight patients treated with 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel over 24 and 3 h, respectively, without G-CSF. DLTs during the first two courses of therapy were observed in one of six patients at the 50/175 (losoxantrone/paclitaxel) mg/m2 dose level, two of four patients at the 50/200 mg/m2 dose level, one of four patients at the 50/225 mg/m2 dose level, and two of five patients at the 60/225 mg/m2 dose level. The degree of thrombocytopenia was worse, albeit not statistically significant, when 24-h paclitaxel preceded losoxantrone, with a mean percentage decrement in platelet count during course 1 of 80.7%, compared to 43.8% with the reverse sequence (P = 0.19). Losoxantrone clearance was not significantly altered by the sequence or schedule of paclitaxel. Cardiac toxicity was observed; however, it was not related to total cumulative dose of losoxantrone. An unacceptably high rate of DLTs at the first dose level of 40 mg/m2 losoxantrone and 135 mg/m2 paclitaxel administered as either a 24- or 3-h i.v. infusion precluded dose escalation without G-CSF support. The addition of G-CSF to the regimen permitted further dose escalation without reaching the MTD. Losoxantrone at 50 mg/m2 followed by paclitaxel (3-h i.v. infusion) at 175 mg/m2 with G-CSF support is recommended for further clinical trials. (+info)
Combination of theanine with doxorubicin inhibits hepatic metastasis of M5076 ovarian sarcoma.
(13/20433)
Theanine is a peculiar amino acid existing in green tea leaves, which was previously indicated to enhance the antitumor activity of doxorubicin. In the present study, the effect of combination of theanine with doxorubicin against hepatic metastasis of M5076 ovarian sarcoma was investigated. The primary tumor was significantly reduced by the combined treatment on M5076 transplanted (s.c.) mice. The liver weight of control mice increased to twice the normal level because of hepatic metastasis of M5076. In contrast, the injection of doxorubicin alone or theanine plus doxorubicin suppressed the increase in liver weight and inhibited hepatic metastasis. Moreover, the liver weights and metastasis scores demonstrated that theanine enhanced the inhibition of hepatic metastasis induced by doxorubicin. Furthermore, in vitro experiments indicated that theanine increased the intracellular concentration of doxorubicin remaining in M5076 cells. This action suggests that theanine leads the enhancement of the suppressive efficacy of doxorubicin on hepatic metastasis in vivo. Therefore, it was proved that theanine increased not only the antitumor activity on primary tumor but also the metastasis-suppressive efficacy of doxorubicin. The effect of theanine on the efficacy of antitumor agents is expected to be applicable in clinical cancer chemotherapy. (+info)
Combination interferon-alpha2a and 13-cis-retinoic acid enhances radiosensitization of human malignant glioma cells in vitro.
(14/20433)
We investigated the individual and combined effects of cis-retinoic acid (CRA) and/or IFN-alpha (IFN) and/or radiation therapy (RT) against a human glioma cell line (American Type Culture Collection; U373MG) to evaluate the possible radiosensitization properties of these agents in vitro. Glioma cells were incubated for 24 h in 96-well plates (2 x 10(2) cells/well) in standard culture medium. Sets of U373 (n = 12) were exposed to CRA (3 x 10(6) microM), IFN (25 units/ml), CRA plus IFN, or standard culture medium. After an additional 24 h of incubation, the U373 cells were subjected to increasing radiation doses (up to 16 Gy). Glioma cells were harvested 92 h after irradiation, and cell survival curves were determined from [3H]thymidine incorporation data (over the last 24 h). The experiment was repeated for both the untreated control group and the combined CRA/IFN group. To verify the [3H]thymidine assays, a clonogenic assay was also performed. Single cell suspensions of U373 cells were plated out in six-well plates (n = 3). After chemical and RT treatment, colonies of 50 cells or more were counted, and cell survival curves were generated as fractions of nonirradiated controls. The amount of RT (in Gy) that would cause a 50% survival fraction (lethal dose 50 or LD50) was calculated from the survival curves by regression analysis. The following LD50s were obtained: [table: see text] The results showed that for both the [3H]thymidine incorporation assay and the clonogenic assay, the combination of IFN/CRA rendered U373 cells more susceptible to ionizing radiation than the untreated control or either single agent alone. (+info)
The aromatase inactivator 4-hydroxyandrostenedione (4-OH-A) inhibits tamoxifen metabolism by rat hepatic cytochrome P-450 3A: potential for drug-drug interaction of tamoxifen and 4-OH-A in combined anti-breast cancer therapy.
(15/20433)
Tamoxifen (tam), an anti-breast cancer agent, is metabolized into tam-N-oxide by the hepatic flavin-containing monooxygenase and into N-desmethyl- and 4-hydroxy-tam by cytochrome P-450s (CYPs). Additionally, tam is metabolically activated by hepatic CYP3A, forming a reactive intermediate that binds covalently to proteins. Tam and 4-hydroxyandrostenedione (4-OH-A) are currently used to treat breast cancer, and it has been contemplated that 4-OH-A be given concurrently with tam to contravene potential tumor resistance to tam. Because alterations in tam metabolism may influence its therapeutic efficacy, the effect of 4-OH-A on tam metabolism was examined. Incubation of tam with liver microsomes from phenobarbital-treated rats, in the presence of 4-OH-A (10-100 microM), resulted in marked inhibition of tam-N-demethylation and tam covalent binding and in decreased tam-N-oxide accumulation; however, there was no inhibition of the formation of 4-hydroxy-tam and of 3,4-dihydroxytamoxifen. These findings indicate that 4-OH-A inhibits CYP3A, but not P-450(s) that catalyze tam 4-hydroxylation. The diminished tam-N-oxide accumulation could be due to decreased N-oxide formation and/or due to increased N-oxide reduction. Incubation of tam-N-oxide with liver microsomes containing heat-inactivated flavin-containing monooxygenase demonstrated that 4-OH-A increases the accumulation of tam, possibly by diminishing its P-450-mediated metabolism. Kinetic studies indicate that 4-OH-A is a competitive inhibitor of CYP3A, but not a time-dependent inactivator. Consequently, the concurrent treatment of tam and 4-OH-A may result in increased tam half-life and thus could potentiate the therapeutic efficacy of tam and diminish the potential side effects of tam by inhibiting its covalent binding to proteins and possibly to DNA. (+info)
Advances in therapy of multiple myeloma: lessons from acute leukemia.
(16/20433)
This paper traces the lack of progress, until recently, in the treatment of multiple myeloma (MM) to having ignored the principles that led to cure in acute leukemia more than 2 decades ago. Only in the mid-1980s did investigation begin to consider complete remission (CR) a research objective, representing a necessary first step toward cure. The experience with autologous and allogeneic stem cell-supported high-dose therapy is reviewed, demonstrating, in both historically controlled and randomized studies, the validity of the dose-response concept in MM in terms of increased CR rates as well as extended event-free (EFS) and overall survival (OS). Avoidance of hematopoietic stem cell-damaging agents, especially melphalan, nitrosoureas, and ionizing radiation to marrow-containing sites, assures the ability of peripheral stem cell collection of high quality and quantity, providing rapid engraftment so that mortality is well under 5% following high-dose melphalan (200 mg/m2). This treatment can be applied safely to patients even >70 years of age and in the presence of renal failure. Tandem autotransplants after multiregimen induction have yielded CR rates in the 40% range with median durations of EFS and OS of 43 and 62 months, respectively. Certain chromosomal abnormalities (11 and 13; and translocations) represent the dominant adverse prognosticator for EFS and OS, confirmed in over 500 patients including those with prior therapy. Allogeneic transplants, possible in less than 10% of MM patients, are associated with a 50% mortality during the first year and, unfortunately, late relapses; thus, this approach should be reserved for patients with high-risk disease early in their management. A risk-based treatment algorithm that matches a patient's disease risk with the risk of intervention is presently used, followed by bisphosphonate therapy, not only to delay the onset of MM-related bone disease but also to induce tumor cell apoptosis, indirectly or directly, by down-regulation of cytokines with antiapoptotic activities. Although many patients relapse, this author subscribes to his mentor's motto: "Be Prepared for Success!". (+info)