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BioOncology Watch Timely Information for Practicing
Physicians |
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november 2002 NON-HODGKIN'S LYMPHOMA (NHL) Chemotherapy following
radioimmunotherapy. Stephen
Ansell and colleagues at the Mayo Clinic retrospectively evaluated how well
58 NHL patients, who had previously been treated with 90Y
ibritumomab tiuxetan 0.4 mCi/kg (on 5 separate protocols), tolerated
subsequent chemotherapy. The median
number of subsequent regimens was 2 (range, 1-7). Compared to controls who had received chemotherapy rather than 90Y
ibritumomab tiuxetan, no significant difference in toxicity was found. Growth factor support was administered to
16 (28%) patients and 13 (22%) patients were hospitalized for neutropenic
fever and/or thrombocytopenia. Eight
patients successfully underwent autologous stem cell transplantation (ASCT)
with stem cells that had been collected after 90Y ibritumomab
tiuxetan therapy. These findings
demonstrate that chemotherapy and ASCT after 90Y ibritumomab
tiuxetan treatment is feasible and is tolerated with acceptable
toxicity. (Ansell SM, et al. J Clin Oncol 2002;20:3885-3890) INHIBITION OF ANGIOGENESIS Recombinant
human endostatin (rhEndostatin). Preclinical studies of rhEndostatin
demonstrated promising antitumor activity and 2 phase I trials of
intravenously administered rhEndostatin in patients with refractory solid
tumors have been recently reported.
These dose finding studies showed that daily doses of rhEndostatin
ranging from 15 to 600 mg/m2 were well tolerated without notable
treatment-related toxicities. In the
first study (Joseph Eder et al.; N=15) 1 patient achieved a minor response
and 2 patients had stable disease. In
the second study (Roy Herbst et al.; N=26) a daily rhEndostatin dose of 300
mg/m2 was found to result in area under the concentration-time
curves similar to those associated with antitumor activity in preclinical
models. However, no tumor responses
were observed. Analyses of tumor
biopsies revealed increases in tumor cell and endothelial cell apoptosis, but
no relationship between rhEndostatin dose and induction of apoptosis was demonstrated. These studies showed that rhEndostatin was well
tolerated, but only minor antitumor activity was observed. (Eder JP, et al. J Clin Oncol 2002;20:3772-3784; Herbst RS, et al. J Clin Oncol 2002;20:3792-3803; Herbst
RS, et al. J Clin Oncol 2002;20:3804-3814) CHRONIC MYELOGENOUS LEUKEMIA
(CML) SOCS expression confers
resistance to interferon-a (IFN-a). Suppressor of cytokine signaling (SOCS)
proteins are a family of negative regulators of cytokine signaling that are
characterized by a central SH2 domain and a C-terminal SOCS-box. Among these proteins, SOCS1 and SOCS3 are
the most important inhibitors of cytokine signal pathways, including IFN-a. Experiments conducted by Ikuya Sakai and
coworkers at Ehime University School of Medicine (Japan) showed that SOCS3 is
constitutively expressed in most CML cell lines that are resistant to IFN-a as well
as IFN-a
resistant blast cells from patients with CML blast crisis. Moreover, the forced expression of SOCS3
in a CML cell line sensitive to IFN-a (KT-1/A3 cell line) conferred resistance to IFN-a. These results indicate that SOCS3
expression may cause CML cells to be resistant to the effects of IFN-a. (Sakai I, et al. Blood 2002;100:2926-2931) Imatinib mesylate-resistant CML. Mechanisms of acquired resistance to
imatinib mesylate (Gleevec; Novartis Pharmaceuticals) in relapsed CML
patients include BCR-ABL gene amplification and kinase domain mutations, such
as T315I and E255K, which alter the targeted region of the protein and thus
abrogate imatinib mesylate binding.
Targeting other molecular features of the BCR-ABL protein, such as its
dependence on the molecular chaperone heat shock protein 90 (Hsp 90), may
overcome resistance associated with kinase domain mutations. Mercedes Gorre and colleagues tested
hematopoietic cells that expressed T315I or E255K for sensitivity to
inhibitors of Hsp 90 (geldanamycin [GA], a benzoquinone ansamycin, and its
less toxic analogue 17-allylamonogeldanamycin [17-AAG]). Both GA and 17-AAG induced the degradation
of mutant and wild-type BCR-ABL proteins and inhibited cell growth. These findings warrant clinical
investigations of 17-AAG in patients with imatinib mesylate-resistant
Philadelphia chromosome-positive leukemias. (Gorre ME, et al. Blood 2002;100:3041-3048) MULTIPLE MYELOMA Proteasome inhibitor PS-341
demonstrates activity. Richard LeBlanc et al. examined
the dose (range, 0.05 to 1.0 mg/kg) response effects of the proteasome
inhibitor PS-341 (Millenium Pharmaceuticals, Inc.) on tumor cell growth and
survival in a human plasmacytoma xenograft murine model. Inhibition of tumor growth, even some with
complete tumor regression, was observed in PS-341-treated mice. Median
survival times were greater in the PS-341 groups compared to controls (30 and
34 days for the higher dose-treated mice vs. 14 days for controls;
p<0.0001). Analysis of tumors
demonstrated that apoptosis was induced and angiogenesis was decreased by
PS-341. PS-341 was well tolerated at
doses up to 0.5 mg/kg while some mice given 1.0 mg/kg lost weight and became
moribund. These experiments showed
that PS-341 has anti-myeloma activity at doses that were well tolerated in a
murine model. (LeBlanc R, et al. Cancer Res 2002;62:4996-5000) EPOETIN American Society of Clinical
Oncology (ASCO) and American Society of Hematology (ASH) guidelines. Consensus ASCO/ASH guidelines for the use
of epoetin have been published in recent issues of both the Journal of
Clinical Oncology and Blood.
(Rizzo JD, et al. J Clin Oncol
2002;20:4083-4107 and Blood
2002;100:2303-2320) |
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