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BioOncology Watch Timely Information for Practicing
Physicians |
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september 2001 Tumor
Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Preclinical studies. TRAIL induces
apoptosis in tumor cells of diverse origin by interacting with a complex
system of 5 cell surface receptors. Two of these receptors are the death
signal-transducing receptors DR4 and DR5, which transmit proapoptotic signals
via their intracellular domains that activate NF-kB and
Jun N-terminal kinase (JNK) pathways. The other 3 receptors (TRAIL-R3,
TRAIL-R4, and OPG) serve as decoy receptors that block TRAIL-mediated
apoptosis. Lucia Altucci and colleagues showed in NB4 acute promyelocytic
leukemia (APL) cells that retinoids selective for retinoid-acid receptor
(RAR)-a induced
the expression of TRAIL, which induced cell death in both retinoid-sensitive
and retinoid-resistant leukemic cells. Constantine Mitsiades et al induced
apoptosis in human multiple myeloma (MM) cell lines and MM cells freshly
isolated from patients with recombinant human TRAIL (Immunex Corporation).
Apoptosis was induced in cells that were sensitive as well as resistant to
dexamethasone and cytotoxic chemotherapies (doxorubicin, melphalan, and
mitoxantrone) and TRAIL was found to overcome the survival effect of
interleukin-6. Moreover, doxorubicin and NF-kB inhibitors were found to
enhance the effect of TRAIL. In addition, Kimihisa Ichikawa and coworkers
studied a novel anti-DR5 monoclonal antibody, TRA-8, because TRAIL has been
associated with the induction of apoptosis in normal human hepatocytes in
vitro and in mice with severe hepatitis. While both primary
hepatocellular carcinoma cells and a liver cancer cell line were highly susceptible,
TRA-8 did not induce significant cell death in normal human hepatocytes.
These studies demonstrate that TRAIL-based therapies may overcome
conventional drug resistance in cancers and provide a rationale for future
clinical trials. (Altucci L, et al. Nat Med 2001;7:680-686; Mitsiades
CS, et al. Blood 2001;98:795-804; and Ichikawa K, et al. Nat Med
2001;7:954-960) Gemtuzumab
Ozogamicin
Association with hepatic
venoocclusive disease (VOD). Mylotarg (gemtuzumab ozogamicin;
Wyeth-Ayerst Laboratories) has recently been approved for the treatment of
elderly patients with relapsed acute myeloid leukemia (AML). Approximately
20% of patients treated with Mylotarg have developed grade 3 or 4
hyperbilirubinemia and/or liver transaminitis, and hepatic VOD has been
reported in patients undergoing stem cell transplantation (SCT) after
Mylotarg therapy. Francis Giles and associates assessed the incidence of
hepatic VOD in 119 patients who had received Mylotarg-containing non-SCT
regimens. Fourteen patients (12%) developed VOD; of these patients, 5 (36%)
had not received prior cytotoxic chemotherapy, including 2 patients treated
with single-agent Mylotarg therapy. Twelve (86%) of the 14 patients died,
however the relative contribution of VOD, concurrent leukemia, and/or sepsis
to death was difficult to assess. Thus, risk factors for VOD should be
evaluated prior to the initiation of treatment with Mylotarg and patients
receiving Mylotarg should be monitored closely for VOD. (Giles FJ, et al. Cancer
2001;92:406-413) Prostate Cancer
Bispecific antibody therapy. MDX-H210
(Medarex, Inc.) is a bispecific antibody directed against HER2 and CD64 (type
I Fc receptor found on monocytes/macrophages and activated neutrophils). In
vitro MDX-H210 has been shown to induce antibody-dependent cellular
cytotoxicity (ADCC) against HER2-positive targets. In addition, GM-CSF can
augment monocyte anti-tumor function and increase CD64 expression, thus
enhancing ADCC. ND James and colleagues treated 25 patients with
HER2-positive hormone-refractory advanced prostate cancer with MDX-H210 (15 mg/m2/day
intravenously) and GM-CSF (5 mg/m2/day
subcutaneously) for 4 days weekly for 6 weeks. Median duration of follow-up
was 105+ days (range, 21-188 days). Two grade 4 adverse events (heart failure
and dyspnea) and one grade 3 event (allergic reaction) resulted in drug
discontinuations. Seven (35%) of 20 evaluable patients had a >50% decrease
in the serum PSA level and 7 (58%) of 12 patients with evaluable pain had
improvements in pain scores. These results indicate that MDX-H210, in
combination with GM-CSF, is active in hormone refractory HER2+ prostate
cancer and is well tolerated. (James ND, et al. Br J Cancer
2001;85:152-156) Multiple
Myeloma (MM)
Vascular endothelial growth
factor (VEGF) effects. VEGF is expressed on and secreted by MM cells and
bone marrow stromal cells. Klaus Podar et al studied the direct effects of
VEGF on a dexamethasone-sensitive myeloma cell line (MM.1S) and MM and plasma
cell leukemia cells obtained from patients. They showed that VEGF triggers
myeloma cell proliferation and migration. Cellular proliferation was induced
through a protein kinase C-dependent Raf-1-MEK-extracellular signal-regulated
protein kinase pathway and migration via a protein kinase C-dependent
pathway. These findings suggest that VEGF is a potential target for novel
therapies for MM. (Podar K, et al. Blood 2001;98:428-435) Tumor
Antigen Identification
Lethality-based selection of
recombinant genes. Ernest Smith and coworkers describe their methods
for the construction of representative cDNA libraries in a poxvirus vector.
This technology allows for the application of lethality-based selection
strategies because fully packaged and infectious poxvirus can be recovered
from cells that have undergone lytic or apoptotic death. In contrast,
plasmid- and retrovirus-based mammalian expression vectors cannot be readily
recovered from cells that are not actively dividing. They have used this
strategy to select a gene that encodes a cytotoxic T-cell target antigen
common to several independently derived tumors. This vector system may also
be utilized to express and select human antibodies in mammalian cells and for
selection of genes that regulate the terminal differentiation of stem cells.
(Smith ES, et al. Nat Med 2001;7:967-972) |
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