Abstract from the "Lymphoma... The Next Questions"
Conference,October 21-23, Palm Desert, CA
Special thanks to the MD Anderson Cancer Center
and Imedex USA
Novel strategies are needed to improve the prognosis of
patients with lymphomas. One approach is to identify new drugs with
unique mechanisms of action. Compound GW506U78, the pro-drug for
arabinosyl-guanine, is an exciting new purine analog, particularly for
T-cell malignancies. Responses have been seen in T-cell non-Hodgkin's
lymphoma (T-NHL), T-cell chronic leukemia, and also in B-NHL. Clinical
trials are ongoing for patients with T-lymphoblastic lymphoma, T-acute
lymphocytic leukemia (T-ALL) and other lymphoid malignancies. This
agent appears to induce responses in about a third of patients with relapsed
or refractory chronic lymphocytic leukemia (CLL). A multicenter study
is accruing patients with CLL who have failed both fludarabine and an alkylating
agent. Neurotoxicity that was problematic early during the conduct
of the study, has not been encountered following modifications in dose
and schedule.
Preliminary results with the pyrimidine analog gemcitabine
suggest a 50% response rate in relapsed and refractory Hodgkin's disease.
A recent study reported a response rate of under 20% in relapsed aggressive
NHL. The potential role of this agent remains to be defined.
Other agents which have undergone clinical testing include
the topoisomerase I inhibitors (topotecan, irinotecan, 9-amino-camptothecin).
When used as single agents in previously treated patients, the overall
response rates have been in the range of 20-25%, with few complete remissions.
Oxaliplatin is a third generation platinum derivative
which is not affected bythe same mechanisms of drug resistance. Preliminary
studies suggest a 40% response rate in NHL and further testing is ongoing.
New and interesting agents in clinical trials are retinoids
and arsenicals which induce apoptosis, and the signal transduction modulators,
bryostatin and UCN-01. Bryostatin exhibits in vitro synergy
with other agents, including vincristine and the dolostatins, small peptides
which cause cell arrest by binding to tubulin. Phase II trials of
the dolostatins are underway in NHL as single agents and in combination
with bryostatin. Flavopiridol is a semisynthetic flavone derivative
that is active against cycling and non-cycling cells, and exhibits sequence
specific synergy with cell cycle specific agents. It induces apoptosis
and inhibits a variety of cyclins, including D1, which is implicated in
the pathogenesis of mantle cell NHL (MCL). Clinical trials are assessing
the activity of this drug in MCL and other lymphomas. UCN-01 not
only inhibits protein kinase c, but also modulates the G1 checkpoint. In
vitro synergy has been demonstrated with fludarabine and a phase I
trial of this combination is ongoing at the National Cancer Institute.
Depsipeptide is a histone deacetylase inhibitor with selective
activity against leukemia cell lines. When incubated with CLL cells
in
, there is no effect on bcl-2, but there is an increase in bax and
decreased expression of p27, overexpression of the latter being associated
with a poor prognosis.
There is an increasing body of evidence which implicates
angiogenesis in hematologic malignancies such as multiple myeloma and lymphoma.
B-cell NHL tissue and Burkitt's cells were angiogenic, with no apparent
relationship to grade or phenotype. There has been an inverse correlation
between increased urinary basic fibroblast growth factor (bFGF) and survival.
Increased cellular bFGF has been associated with fludarabine resistance
in CLL cells. Microvessel density increases with increasing grade,
and a high serum vascular endothelial growth factor (VEGF) level at diagnosis
has been correlated with a poor clinical outcome. Several angiogenesis
inhibitors are currently in clinical trials, including thalidomide and
SU5416, and studies in NHL will be active shortly.
Recent studies on Ras have led to the identification
of compounds called farnesyl-transferase inhibitors (FTIs). The Ras
proteins have a pivotal role in signal transduction that send messages
from the cell membrane to the nucleus. These agents block the membrane
association of Ras proteins, which may prevent the gene from transforming
cells. This observation has suggested the possibility that FTIs may
be useful in cancer prevention as well as cancer therapy.
Unfortunately, patients often receive new investigational
drugs after failing extensive prior therapy, when they are least likely
to respond. In addition, most drugs are administered as single agents,
which may not be the optimal way to use them. Negative results in
preliminary trials may lead to the premature discarding of potentially
valuable agents. Future strategies must involve close collaboration
between laboratory scientists and clinical researchers to identify the
appropriate therapeutic targets and to design rational drug combinations.
The goal of clinical research must be to increase the likelihood of cure
of patients with lymphomas.
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