Background: Pegylated liposomal doxorubicin (Doxil®) has been reported to cause immediate hypersensitivity reactions (HSRs) that cannot be explained as IgE-mediated (type I) allergy. Previous in ...vitro and animal studies indicated that activation of the complement (C) system might play a causal role in the process, a proposal that has not been tested in humans to date. Patients and methods: Patients with solid tumors (n = 29) treated for the first time with Doxil were evaluated for HSRs and concurrent C activation. HSRs were classified from mild to severe, while C activation was estimated by serial measurement of plasma C terminal complex (SC5b-9) levels. Increases in SC5b-9 were compared in patients with or without reactions, and were correlated with Doxil dose rate. Results: Moderate to severe HSRs occurred in 45% of patients. Plasma SC5b-9 at 10 min after infusion was significantly elevated in 92% of reactor patients versus 56% in the non-reactor group, and the rise was greater in reactors than in non-reactors. We found significant association between C activation and HSRs, both showing direct correlation with the initial Doxil dose rate. Conclusions: C activation may play a key role in HSRs to Doxil. However, low-level C activation does not necessarily entail clinical symptoms, highlighting the probable involvement of further, as yet unidentified, amplification factors.
The cancer-chemopreventive effects of broccoli may be attributed, in part, to isothiocyanates (ITCs), hydrolysis products of glucosinolates. Glucosinolates are hydrolyzed to their respective ITCs by ...the enzyme myrosinase, which is inactivated by heat. In this study, the metabolic fate of glucosinolates after ingestion of steamed and fresh broccoli was compared in 12 male subjects in a crossover design. During each 48-hour baseline period, no foods containing glucosinolates or ITCs were allowed. The subjects then consumed 200 g of fresh or steamed broccoli; all other dietary sources of ITCs were excluded. Blood and urine samples were collected during the 24-hour period after broccoli consumption. Total ITC equivalents in broccoli and total ITC equivalents in plasma and urine were assayed by high-performance liquid chromatography as the cyclocondensation product of 1,2-benzenedithiol. The content of ITCs in fresh and steamed broccoli after myrosinase treatment was found to be virtually identical (1.1 vs. 1.0 μmol/g wet wt). The average 24-hour urinary excretion of ITC equivalents amounted to 32.3 ± 12.7% and 10.2 ± 5.9% of the amounts ingested for fresh and steamed broccoli, respectively. Approximately 40% of total ITC equivalents in urine, 25.8 ± 13.9 and 6.9 ± 2.5 μmol for fresh and steamed broccoli, respectively, occurred as the N-acetyl-L-cysteine conjugate of sulforaphane (SFN-NAC). Total ITC metabolites in plasma peaked between 0 and 8 hours, whereas urinary excretion of total ITC equivalents and SFN-NAC occurred primarily between 2 and 12 hours. Results of this study indicate that the bioavailability of ITCs from fresh broccoli is approximately three times greater than that from cooked broccoli, in which myrosinase is inactivated. Considering the cancer-chemopreventive potential of ITCs, cooking broccoli may markedly reduce its beneficial effects on health.
Purpose
The potential synergy of modulating platinum-induced DNA damage by combining the proteasome inhibitor bortezomib with oxaliplatin was studied in patients with solid tumors, with special ...attention to avoidance of cumulative neurotoxicity (NT).
Patients and methods
In a 3 + 3 dose escalation design, patients received bortezomib at 1.0–1.5 mg/m
2
on days 1 and 4 and oxaliplatin at 60–85 mg/m
2
on day 1 of a 14-day cycle. NT assessments were performed at the start of every two cycles. Oxaliplatin pharmacokinetics (PK) were determined pre- and post-bortezomib.
Results
Thirty patients were enrolled with 25 (11 men, 14 women) fully evaluable for NT assessments at cycle 2. The median age was 56 years (range 35–74 years); median number of cycles received 2 (range 1–10). At dose levels 2–5 (B 1.3 mg/m
2
), patients manifested NT grades 3 and 4 at a median 3.4 cycles (range 2–9 cycles): 3 had ataxia (one also with sensory neuropathy or neurogenic hypotension, respectively) and 3 had just sensory neuropathy. A 6th dose-level reducing bortezomib to 1.0 mg/m
2
with oxaliplatin 85 mg/m
2
) was explored and no NT or dose limiting toxicities were noted among 7 evaluable patients (5 receiving two or more cycles). Four patients experienced a partial response—one with platinum-resistant ovarian cancer, another with gastroesophageal cancer, another with ampulla of Vater carcinoma, and a patient with cholangiocarcinoma. PK studies at dose levels 1 and 2 showed greater mean ultrafiltrable platinum when oxaliplatin was dosed after bortezomib.
Conclusions
Bortezomib 1.0 mg/m
2
× 2 every 14 days combines safely with oxaliplatin. At higher doses, cumulative NT (i.e., cerebellar signs and sensory neuropathy) occurs at an accelerated pace perhaps from a PK interaction.
We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome ...inhibition obtained.
Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1.
On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma.
Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea.
While epidermal growth factor receptor (EGFR) dysregulation is known to play a critical role in prostate carcinogenesis, there has been no direct evidence indicating EGFR mutations induce ...tumorigenesis in prostate cancer. We previously identified four novel EGFR somatic mutations in the EGFR tyrosine kinase domain of prostate cancer patients: G735S, G796S, E804G and R841K. In this study, we investigated the oncogenic potential of these somatic mutations by establishing stable clonal NIH3T3 cells expressing these four mutations and WT EGFR to determine their ability to increase cell proliferation and invasion. In the absence of the EGF ligand, cell proliferation was readily increased in G735S, G796S and E804G mutants compared to WT EGFR. The addition of EGF ligand greatly increased cell growth and transforming ability of these same EGFR mutants. Matrigel invasion assays showed enhanced invasion with G735S, G796S and E804G mutants. Western blot analysis showed that these EGFR mutations enhanced cell growth and invasion via constitutive and hyperactive tyrosine phosphorylation and led to the activation of mitogen-activated protein kinase (MAPK), signal transducer and activator of transcription 3 (STAT3) and Akt pathways. Our findings demonstrate the oncogenic activation of three novel EGFR somatic missense mutations in prostate cancer. Molecules that regulate the mechanisms of their oncogenic activation represent novel targets for limiting tumor cell progression, and further elucidation of these mutations will have utility in prostate cancer treatment.
ABSTRACT
Pegylated liposomal doxorubicin (Doxil) and 99mTc-HYNIC PEG liposomes (HPL) were reported earlier to cause hypersensitivity reactions (HSRs) in a substantial percentage of patients treated ...i.v. with these formulations. Here we report that (1) Doxil, HPL, pegylated phosphatidylethanolamine (PEG-PE)-containing empty liposomes matched with Doxil and HPL in size and lipid composition, and phosphatidylglycerol (PG)-containing negatively charged vesicles were potent C activators in human serum in vitro, whereas small neutral liposomes caused no C activation. (2) Doxil and other size-matched PEG-PE and or PG-containing liposomes also caused massive cardiopulmonary distress with anaphylactoid shock in pigs via C activation, whereas equivalent neutral liposomes caused no hemodynamic changes. (3) A clinical study showed more frequent and greater C activation in patients displaying HSR than in non-reactive patients. These data suggest that liposome-induced HSRs in susceptible individuals may be due to C activation, which, in turn, is due to the presence of negatively charged PEG-PE in these vesicles.
Ionizing radiation can reduce tumor growth outside the field of radiation, known as the abscopal effect. Although it has been reported in multiple malignancies, the abscopal effect remains a rare and ...poorly understood event. Ionizing radiation generates inflammatory signals and, in principle, could provide both tumor-specific antigens from dying cells and maturation stimuli that are necessary for dendritic cells' activation of tumor-specific T cells. We therefore tested the hypothesis that the abscopal effect elicited by radiation is immune mediated. This was directly tested by enhancing the number of available dendritic cells using the growth factor Flt3-Ligand (Flt3-L).
Mice bearing a syngeneic mammary carcinoma, 67NR, in both flanks were treated with Flt3-L daily for 10 days after local radiation therapy (RT) to only 1 of the 2 tumors at a single dose of 2 or 6 Gy. The second nonirradiated tumor was used as indicator of the abscopal effect. Data were analyzed using repeated measures regression.
RT alone led to growth delay exclusively of the irradiated 67NR tumor, as expected. Surprisingly, growth of the nonirradiated tumor was also impaired by the combination of RT and Flt3-L. As control, Flt3-L had no effect without RT. Importantly, the abscopal effect was shown to be tumor specific, because growth of a nonirradiated A20 lymphoma in the same mice containing a treated 67NR tumor was not affected. Moreover, no growth delay of nonirradiated 67NR tumors was observed when T cell deficient (nude) mice were treated with RT plus Flt3-L.
These results demonstrate that the abscopal effect is in part immune mediated and that T cells are required to mediate distant tumor inhibition induced by radiation.
Ovarian cancer is the leading cause of gynecologic cancer deaths in the U.S. The concept of intraperitoneal drug delivery for therapy of intraperitoneal cancers, such as ovarian cancer, arose in the ...1960s. The field of intraperitoneal cisplatin therapy for ovarian cancer was initiated in the late 1970s and early 1980s. The markedly improved survival data resulting from a phase III trial of intraperitoneal cisplatin for ovarian cancer in early 2006 led to an NCI Clinical Announcement and a Gynecologic Oncology Group-sponsored workshop on intraperitoneal therapy in January, 2006, in San Diego, California. The proceedings of this workshop summarize both research trial results and practical implementation issues associated with intraperitoneal therapy discussed at this workshop.
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