Aptosyn®(Exisulind)
Update 4/16/06
The Cancer and Leukemia Group B (CALGB) performed a
phase II, multicenter clinical trial that added Exisulind to the
docetaxel/estramustine combination.
Exisulind, is a sulindac derivative with antineoplastic
properties.[2] CALGB 90004 observed a significant degree of toxicity
with the triple-agent regimen, docetaxel/ estramustine/ exisulind. Most
noteworthy was the reported 10% rate of thromboembolism in the absence
of survival or response rate improvements.[1] Another phase II study of
every-3-week docetaxel plus exisulind reported a similar response rate
to the historical response of docetaxel alone.[2] These results make it
seem unlikely that exisulind will be further studied in HRPC.
1. Dawson NA, Halabi S, Biggs DD, Kelly WK, Small E. A
phase II study of estramustine (E), docetaxel (D), and exisulind in
hormone-refractory prostate cancer (HRPC): toxicity results of CALGB
90004. Program and abstracts of the 2005 Multidisciplinary Prostate
Cancer Symposium; February 17-19, 2005; Orlando, Florida. Abstract 289.
2. Ryan CW, Stadler WM, Vogelzang NJ. A phase I/II
dose-escalation study of exisulind and docetaxel in patients with
hormone-refractory prostate cancer. BJU Int. 2005;95:963-968.
Update added 4/16/06 by H. Hansen
Note: OSI Pharmaceuticals has acquired Cell Pathways.
Hence drugs that formerly had designations such as CP461 now have OSI461
names.
See also
Sulindac for information on how the drug
sulindac relates to exisulind. The following paper covers Aptosyn®
(exisulind). There is a newer, more potent forms of SAAND
technology called OSI461®.
Net: this drug might have promise, but
for HRPC patients it has yet to be demonstrated. However, in time,
there may be something worthwhile for treating HRPC patients with this
class of drugs -- either by themselves or in combination with
chemotherapy.
As of this writing, OSI is
developing Aptosyn®
for NSCLC (phase III) and mentions various investigator sponsored trials
are also going on for other cancers including prostate (see
www.clinicaltrials.gov.
So far, no clinical trials
have been completed or published data made available for hrpc patients,
to this writer's knowledge.
What has been shown, so
far, is that exisulind will increase the PSA doubling time for men who
have a recurrence of prostate cancer as shown by a rising PSA after a
radical prostatectomy. This was presented at ASCO
2002, Abstract No. 733, by Prager et al, "Long-term use of exisulind in
men with prostate cancer following radical prostatectomy." The increase in median PSADT in high risk,
i.e., high risk for developing bone metastases, patients who received exisulind for the entire 24 months
was significant statistically. PSADT increased from 5.6
months pre-study to 12.6 months. Doubling times (medians) increased from
13.3 months to 19.6 months in the intermediate risk group (not
significant statistically.) This longer study period had adverse
events which included asthenia, abdominal pain, diarrhea, and elevation of transaminases
-- most being mild in severity. The serious adverse events were seen in
3 patients with biliary events.
The clinical trial
portfolio of OSI is
given at this site
http://www.osip.com/OSI/clinical.asp?id=74. OSI461 is listed as
being tested for PCa.
Some information on
Aptosyn® is found at
http://www.osip.com/OSI/clinical.asp?id=69 -- there are prostate
cancer trials available.
A preliminary
report on this drug combination was presented at ASCO 2002, abstract #2460
by Diane E
Pruitt-Scott, Christopher W Ryan, Walter M Stadler, Nicholas J
Vogelzang, University of Chicago, Chicago, IL. "Exisulind (EXI) plus
docetaxel (DOC) for hormone-refractory prostate cancer (HRPC)".
This was a phase I trial.
They note that some synergism was seen between docetaxel and exisulind
in pre-clinical studies. The presented results, don't show that as
there was no randomization. The trial used exisulind at doses up
to 500mg/day for 21 days; then docetaxel every 21 days at a dose of
60-75mg/m2 along with dexamethasone. All the
usual toxicities associated with docetaxel were seen. It isn't
clear that adding exisulind increased any toxicity level -- at least
from the abstract. Here's the PSA response (>50% decline) --
PSA response was observed in 7 of 15
patients (44%) and a
measurable partial response in 2/6 (33%) evaluable patients.
The 44% PSA response rate is
not much different than single agent docetaxel which range from
35-46% and the measurable response is also comparable to single
agent docetaxel. The number of patients is small and 47% had
had prior chemotherapy.
A detailed review of the scientific
background relating to the Selective Apoptotic Antineoplastic Drug (SAAND)
Technology, can be gained by reading the published literature. Briefly: Aptosyn®
is OSI's 1st
generation SAAND. Cancer cells have a form of 'immortality' as a
result of damage to the genetic and chemical messengers that mediate the
balance of cell proliferation and cell death(apoptosis). Examples of
cell death(apoptosis) protein regulator cells are p53, Bcl2, and Bax.
SAANDs work through a fundamental apoptosis pathway -- restoring
signaling and hence allowing cell death to reoccur. The 'S' in SAAND
stands for selective -- meaning that it is the cancer cells that are
targeted, not normal cells.
Besides the clinical work for Aptosyn®,
OSI is developing OSI-461, said to be 100x more potent than Aptosyn®.
Note: potency is measured for cGMP PDE inhibition.
OSI-461 is in a clinical
trial with the title, "A Phase II Pilot Study of CP461 in Prostate
Cancer Patients with Measurable Disease."
Other References
Goluboff ET, Prager D, Rukstalis D, Giantonio B, Madorsky M, Barken I,
Weinstein B, Partin AW, Olsson CA: Safety And Efficacy Of Exisulind In
The Treatment Of Recurrent Prostate Cancer Following Radical
Prostatectomy. Jr of Urology 2001:166; 882-886.
Goluboff E.: Exisulind, A Selective Apoptotic Antineoplastic Drug (SAAND). Expert Opinion on Investigational Drugs. 2001: 10 (10):
1875-1883.
Thompson WJ, et. al: Apoptosis in human prostate cancer cells shows
enhanced sensitivity to taxol in the presence of exisulind. Annals of
Oncology 2000;11(4):634P, 139.
Duffy CP, et. al: Enhancement of chemotherapeutic drug toxicity to human
tumour cells in vitro by a subset of non-steroidal anti-inflammatory
drugs (NSAIDS). European Journal of Cancer 1998;34(8):1250-1259.
Goluboff ET, Shabsigh A, Saidi JA, Weinstein IB, Mitra N, Heitjan D,
Piazza GA, Pamukcu R, Buttyan R, Olsson CA: Exisulind (Sulindac Sulfone)
Suppresses Growth Of Human Prostate Cancer In A Nude Mouse Xenograft
Model By Increasing Apoptosis. Urology 1999;53: 440-445.
Lim
JT, Piazza GA, Han EKH, Delohery TM, Li H, Finn TS, Buttyan R, Yamamoto
H, Sperl GJ, Brendel K, Gross PH, Pamukcu R, Weinstein IB: Sulindac
Derivatives Inhibit Growth And Induce Apoptosis In Human Prostate Cancer
Cell Lines. Biochem Pharmacol 1999;58:1097-1107.
Piazza GA, Rahm AK, Finn TS, Fryer BH, Li H, Stoumen AL, Pamukcu R,
Ahnen DJ: Apoptosis Primarily Accounts For The Growth-Inhibitory
Properties Of Sulindac Metabolites And Involves A Mechanism That Is
Independent Of Cyclooxygenase Inhibition, Cell Cycle Arrest, And P53
Induction. Cancer Research 1997;57: 2452-2459.
