Haematologica 2003 - Supplements

degrade OPG in the same way as myeloma cells do. Plasma cells
in bone marrow biopsies from myeloma patients stained positive
for OPG. The binding, internalisation and degradation of OPG by
myeloma cells may contribute to the reduced OPG levels
observed in the bone marrow of multiple myeloma patients.
Furthermore, OPG may be removed from both osteoblast surfaces
as well as the bone marrow microenvironment by the presence of
myeloma derived soluble heparan sulphates.
Alternatively, myeloma cells may interfere with osteoblast
expression of OPG, either by affecting OPG synthesis and
secretion, or by affecting osteoblast differentiation and
maturation. The opportunities in manipulating functional bone
marrow OPG levels in patient treatment will be discussed.
References:
Yamaguchi K, Kinosaki M, Goto M, et al. Characterization of
structural domains of human osteoclastogenesis inhibitory factor.
J Biol Chem.; 273(9): 5117-23.
Pearse RN, Sordillo EM, Yaccoby S, et al. Multiple myeloma
disrups the TRANCE/osteoprotegerin cytokine axis to trigger
bone destruction and promote tumor progression. Proc Natl Acad
Sci USA 2001; 98: 11581-6.
Giuliani N, Bataille R, Mancini C, et al. Myeloma cells induce
imbalance in the osteoprotegerin ligand system in the human
bone marrow environment. Blood 2001; 98: 3527-33.
Seidel C, Hjertner Ø, Abildgaard N, et al. Serum osteoprotegerin
levels are reduced in patients with multiple myeloma with lytic
bone disease. Blood 2001; 98; 2268-71.
Standal T, Seidel C, Hjertner O, et al. Osteoprotegerin is bound,
internalized, and degraded by multiple myeloma cells.Blood.
2002; 100: 3002-7.
P12.2.3
BCL-2 ANTISENSE THERAPY IN MULTIPLE MYELOMA
Asher Chanan-Khan
Roswell Park Cancer Institute, Buffalo, NY
Oblimersen sodium (G3139, Genasense) is a novel new agent
designed to restore the intrinsic programmed cell death (apoptosis)
pathway through down regulation of Bcl-2 protein.
Overexpression of Bcl-2 oncoprotein was first detected in non-
Hodgkin’s lymphoma (NHL) bearing the t(14:18) chromosomal
translocation. This translocation juxtaposes the bcl-2 gene adjacent
to the immunoglobulin gene on chromosome 14, which leads to
transcription of a chimeric Bcl-2-IgH mRNA and subsequent
increased production of the Bcl-2 anti-apoptotic protein.
The Bcl-2 protein family is a critical regulator of apoptosis through
modulation of cytochrome-c release from the mitochondria. Over
production of Bcl-2 protein results in stabilization of the inner
mitochondrial membrane and inhibition of the release of
mitochondrial cytochrome-c. This dampens the effect of external
apoptotic signals (chemotherapy, radiotherapy or antibody therapy)
on cancer cells. Reduction of Bcl-2 protein within the tumor cell
can potentially restore this apoptotic pathway and re-sensitize
malignant cells to undergo apoptosis.
Oblimersen is a phosphorothioate antisense oligonucleotide (ASO)
complimentary to the first 6 codons of the open reading frame of
human bcl-2 mRNA. Oblimersen forms a hetroduplex with the Bcl-
2 mRNA by the Watson-Crick base-paring phenomenon.
Formation of this aberrant hetroduplex in the cytosol engages
RNAse-H that cleaves the mRNA and frees the stabilized ASO for
catalytic hybridization with other strands of bcl-2 mRNA. This
pre-protein therapy reduces the intracellular pool of bcl-2 mRNA
and decreases production of Bcl-2 protein.
Malignant plasma cells overexpress Bcl-2 oncoprotein. Feinman et
al reported dexamethasone resistance with overexpression of Bcl-2
in human myeloma cells. Oblimersen down regulates both Bcl-2
mRNA and protein in human myeloma cell lines as well as ex vivo
malignant plasma cells isolated from patients with multiple
myeloma in a sequence specific manner. Oblimersen enhanced
antitumor activity when combined with dexamethasone or
chemotherapy in these model systems [1, 2]. No such enhancement
was seen with control phosphorothioate oligonucleotides.
Phase I and II studies of oblimersen conducted in NHL, CLL and
other solid tumors have utilized either subcutaneous (SC) and
intravenous (IV) routes of administration and suggested that the drug
is active alone in some lymphoid tumors and may enhance the
activity of chemotherapy in other diseases [3]. NHL patients
receiving a 14 day subcutaneous infusion had a maximal tolerated
dose (MTD) of 4.1 mg/kg/d [4]. Patients with CLL treated with a 5-7
day intravenous infusion had a MTD of 3 mg/kg/d. Dose-limiting
toxicities were fever and hypotension. The MTD for AML,
myeloma, and solid tumor patients exceeds 7 mg/kg/day for up to 7-
day infusions.
Transient common toxicities associated with oblimersen include
fatigue, fever and thrombocytopenia. Elevated transaminases were
seen in patients receiving 14-day infusions. Tumor lysis has been
observed in CLL patients. In our experience oblimersen infusions
are easily administered and well tolerated in MM patients.
Ongoing clinical trials are exploring the role of Bcl-2 antisense as
chemosensitizing agent in various malignant disorders including,
melanoma, lung cancer, prostate cancer, NHL, CLL, AML and
MM. A phase I trial of oblimersen is underway in Waldenstrom’s
Macroglobulinemia [5]. A phase III trial comparing dexamethasone
vs. oblimersen in combination with dexamethasone in refractory
and relapsed MM is near completion. Over 200 pts have been
enrolled. In this trial oblimersen sodium is a given at a dose of
7mg/kg/day for seven days, Dexamethasone 40 mg orally, is given
for 4 days beginning on day 4. Patients with creatinine 100,000/uL, and up to 6 prior therapies (including
autologous stem cell transplant) are eligible. Two other phase 2
trials with oblimersen are underway in MM. In one trial VAD
resistant patients are rechallenged with VAD after treatment with
oblimersen, thus evaluating the ability of oblimersen to reverse
resistance to chemotherapy. The second trial is evaluating a
regimen of dexamethasone, thalidomide, and oblimersen. Results
of these trials will guide further studies and development of
oblimersen therapy in MM.
Reference:
1. Liu, Q. and Y. Gazitt, Potentiation of dexamethasone, taxol
and Ad-p53-induced apoptosis by Bcl-2 anti-sense
oligodeoxynucleotides in drug-resistant multiple myeloma cells.
Blood, 2003.
2. van de Donk, N.W., et al., Chemosensitization of myeloma
plasma cells by an antisense-mediated downregulation of Bcl-2
protein. Leukemia, 2003. 17(1): p. 211-9.
3. Klasa, R.J., et al., Oblimersen Bcl-2 antisense: facilitating
apoptosis in anticancer treatment. Antisense Nucleic Acid Drug
Dev, 2002. 12(3): p. 193-213.
4. Waters, J.S., et al., Phase I clinical and pharmacokinetic
study of bcl-2 antisense oligonucleotide therapy in patients with
non-Hodgkin's lymphoma. J Clin Oncol, 2000. 18(9): p. 1812-23.
5. Frankel, S.R., G3139 (Bel-2 Antisense Oligonucleotide)
Therapy in Waldenstrom's Macroglobulinemia: A Targeted
Approach to Enhance Apoptosis. Semin Oncol, 2003. 30((2)): p.
in press.
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