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Evaluation of sulindacas a therapy for hrpc
Terminology There is a confusing array of names for sulindac, compounded by the fact that it metabolizes to two other chemicals. In this evaluation I use the name sulindac, as the generic name for the drug to be taken. And I use sulindac sulfone (abbreviated SS) and sulindac sulfide for the two metabolites. To add to the confusion, there are many journal articles on SS alone, but many others on sulindac with both metabolites. I have generally combined these discussions since dosing with sulindac results in production of SS inside the body. Sulindac = sulindac sulfoxide = Clinoril, which metabolizes to Compound 1: Sulindac sulfone (SS) = exisulind = Aptosyn = FGN-1and Compound 2: Sulindac sulfide. Summary opinion The hope for sulindac is that it will slow—perhaps stabilize—the progression of hrpc. The mechanisms reported for this drug and its metabolites are induction of apoptosis, inhibition of cell proliferation, and anti-angiogenesis. The current wide interest in this drug comes from the development of the metabolite sulindac sulfone by Cell Pathways, Inc. (CPI), for successfully treating a precancerous colon condition known as familial adenamatous polyposis; that metabolite, trade-named Aptosyn, is also being tested for pca. Because Aptosyn is not easily available, this paper focuses on the parent chemical, sulindac, a drug available today by prescription. There are—as yet—no human trials reported for hrpc, although there is a wealth of reports for earlier stage pca and for several other cancers. The same drug demonstrated slowing of the PSADT among men with recurrent (but not metastatic) pca. The drug side effects are reported to be readily manageable. The most serious risk is GI irritation, because this is an NSAID, just like aspirin. Sulindac is available now as a generic prescription at a cost of $50-$75/mo. When it is ingested, sulindac metabolizes to two derivatives, most of which is SS. The published reports attribute most of the anti-cancer activity to this metabolite. There are anecdotal cases that suggest effectiveness in hormone-sensitive and –insensitive pca. For us, the biggest unanswered question about sulindac and its metabolites is whether they will be effective against advanced, metastatic pca. Given the manageable toxicity, the present availability, and the positive indications of effectiveness, sulindac looks like a drug worth considering. Additionally, it appears to be usable with other cancer therapies. If Aptosyn is licensed and if the pca trials pan out, especially for the Aptosyn derivatives (CP248, CP-461), which are claimed to be more potent, I would consider going to that and comparing the results with sulindac. Therapy The metabolite SS is taken orally twice a day. Likewise, sulindac would follow the same dosing schedule; see below. If the therapy is successful, trials to date indicate that sulindac should be continued indefinitely since this drug suppresses—but does not cure--cancer. No specific treatment period has been suggested in any of the articles. One would need to be guided by the test and scan results, as well as the side effects. If one reviews the side effects in the PDR, there seems to be no reason why sulindac can’t be used with many other drugs. [PDR] Since there is a risk of GI bleeding, caution must be exercised when using sulindac with blood thinners or other NSAIDs. One of the trials sponsored by CPI combines SS with Taxotere; there is some suggestion—not proven in humans with hrpc—that such combinations will prove synergistic. The main point, however, is that combining SS with other drugs sensibly appears to be an acceptable strategy. How does it work…in the body…in cancerous cells…in normal cells? To quote the PDR, "…Following absorption, sulindac undergoes two major biotransformations—reversible reduction to the sulfide metabolite, and irreversible oxidation to the sulfone metabolite (SS)." [PDR] SS is called—by CPI--a "selective apoptotic anti-neoplastic drug (SAAND)." Sulindac, the precursor, is simply an NSAID, much like aspirin. Reports in the literature indicate that sulindac and its metabolites have three beneficial effects: induction of apoptosis, inhibition of cell proliferation, and anti-angiogenesis. Although most reports focus on SS, there are many reports that attribute the benefits to both metabolites. The key action of sulindac is induction of apoptosis. The enzyme guanylate cyclase is the signal to the cell to begin the process of apoptosis. This message is blocked by the counteracting enzyme cGMP-PDE (cyclic guanosine monophosphate-phosphodiesterase), which is overexpressed in colon cancer cells (and, presumably, in pca). SS blocks cGMP-PDE so that the apoptotic signal can proceed through the series of enzyme reactions that culminate in apoptosis. [CPI] Sulindac caused regression of colon cancer cells in lab experiments and prevented their recurrence. The action was independent of p53 gene expression, COX enzymes, and Bcl-2, although there are conflicting reports about inhibiting of COX enzymes and proteins. A laboratory study (in vitro) indicated that sulindac causes growth inhibition in both normal and cancerous prostate cells, but that apoptosis is induced only in the cancerous cells, not in the normal cells. The mechanism of this growth inhibition was not described. [LIM] A laboratory test of xenograft lung tumors in mice showed that "sulindac sulfoxide and sulfone statistically inhibited angiogenesis." [SKOPINSKA-ROZEWSKA] What evidence exists that this works in men with HRPC? With PSA as the indicator, a safety/efficacy study was made of 96 men (no mets or HT; PSA 0.4 to 15), who exhibited PSA progression following RP. They were randomized to 250 mg SS b.i.d. or placebo orally for up to 12 months. In what the investigators considered to be a "high risk" group, those taking a placebo (6 pts.) experienced a mean PSA increase of 3.10 ng/ml. Those taking SS (9 pts.) experienced a PSA increase of 1.15. This slowing in the rate of progression was not as dramatic in the lower risk groups. The drug was "well tolerated." (GOLUBOFF] A variety of laboratory studies have been reported, as well as clinical studies of the originally targeted FAP. Indications of effectiveness have been reported for other cancers as well. No trials of sulindac or SS with hrpc have been published yet. One of our hrpc internet correspondents was able to get Aptosyn on a compassionate use basis. In his case, PSA had been found to be an unreliable marker of cancer status. So he gets bone scans to monitor progress. Baseline scans were made at the beginning of the treatment, then 7 months later. During this treatment period, he was taking 250 mg b.i.d. each day. During that period, there has been no apparent disease progression. An increase in liver enzymes was attributed to the Aptosyn; he is taking silymarin to protect his liver. A second correspondent used sulindac, 300 mg b.i.d. daily. He is NOT hrpc. He experienced a lengthened doubling of his PSADT from 7 months up to about 14 months over a dosing period of 9 months. He also used Lipitor and curcumin as adjuvant treatments (based on his adaptation of a Life Extension Foundation protocol). He has had no problem with side effects. What other uses does this drug have? Sulindac (Clinoril) is an NSAID that is used as an analgesis and as an anti-inflammatory agent for arthritis. This application has nothing to do with fighting cancer. Most—but not all--reports indicate that sulindac does not inhibit either COX-1 or COX-2; so it is not necessarily a replacement for Celebrex or Vioxx. What drugs are similar in function? Sulindac is an NSAID. One article compares it with indomethacin, another NSAID. What are the side effects? The side effects of sulindac are the same as other NSAIDs. GI toxicity is possible and potentially serious; watch for ulcers and GI bleeding. It is an inhibitor of platelet function. Kidney and liver functions should be monitored. The PDR report should be reviewed. [PDR] In one toxicity study, 8 patients with unidentified, advanced cancers were treated with taxotere (normal 3-week dose) and SS (100-300 mg b.i.d. each day) over 420 days. The most common toxicities were grade 1 to 2 fatigue and dyspepsia. The investigators concluded that the combination was "well tolerated." [PIERSON] In another toxicity study, patients with FAP were treated with oral doses of SS of 200-400 mg b.i.d. daily. "Reversible hepatic dysfunction was noted in four of six patients treated at the 400-mg p.o., twice-a-day dose level, but in only one to two of six patients treated at each of the lower dose levels. The serum half-life of exisulind was 6-9 h; little drug accumulation was noted over time….The maximum safe dose of exisulind is 300 mg p.o. twice a day in patients with subtotal colectomies." [ VAN STOLK] In a Ph. 1-2 trial, 11 patients with FAP received the drug for 36-50 months. In addition to the trend of reduced polyp formation, SS was "well tolerated by all patients." The patients were still on treatment as of 10/99. [GRIFFITHS] What is the status in the drug development pipeline? When will it be available? Sulindac is available today, by prescription, as either a generic or as Clinoril. Aptosyn is in the FDA licensing pipeline, with no indication of how soon, or even whether, it will be approved. Some individuals have obtained it on a "compassionate use" basis, which requires Cell Pathways and FDA approval. Who is the pharmaceutical? Sponsoring institution? Lead scientist? Sulindac is generic. Clinoril is manufactured by Merck. Cell Pathways, Inc., Horsham, PA, is the developer and trial sponsor for Aptosyn. What are the current trials? Contacts? There are no current Clinoril or sulindac trials; this is an approved drug. Cell Pathways has 10 trials listed for Aptosyn on its web site www.cellpathways.com. A Ph. 2 trial is listed as "open" for pca. A Ph. 1-2 hrpc trial was started for taxotere and Aptosyn; however, one of our contacts reports that this trial was suspended. Call 877-231-4567 for trial information. What is the dosage? Considering all the dosages reported in all the reports, the safe maximum for SS should also be a safe maximum for sulindac. Therefore, a dose range is suggested of 200-300 mg b.i.d every day WITH FOOD. No dosing duration has been defined; therefore, the duration should be based on the experienced side effects combined with the results of tests and scans. As usual, tests should be done at least monthly. What tests are indicated? It is suggested that a baseline PSA value be determined. It is necessary to watch the PSADT to determine if there is a slowing of the doubling time, as this is the primary anticipated benefit. Keep in mind that even a slowing in doubling time is a way to extend survival. A baseline bone scan and MRI would also be advisable to watch for disease spread that is not marked by PSA. Liver and kidney function should be watched.
What other drugs are used with this drug? Synergistic effects? Conflicting drugs? Generally, the same precautions that apply to other NSAIDs apply to sulindac. Sulindac should not be used with DMSO. Any use with anti-coagulants should be watched closely as sulindac inhibits platelet function. Aspirin and other NSAIDs can aggravate the GI toxicity; serious bleeding is possible. "Caution should be used if Clinoril is administered concomitantly with methotrexate" as the toxicity may be increased. [PDR] If you use this drug, review the PDR. Where do you obtain it? Cost? Clinoril is Merck’s brand of sulindac ( generic name sulindac sulfoxide); a bottle of 60 200-mg tabs of generic sulindac is about $50. That would be a month’s supply at the dosage of 200 mg b.i.d. A prescription is required. List of references: Cell Pathways, Inc., web site, www.cellpathways.com, 5/15/01. "Clinoril," Physicians’ Desk Reference, 54th ed., Medical Economics Co., Montvale, NJ, 2000, pp. 1756-1758. Goluboff, E., et al., "Exisulind inhibits the progression of prostate cancer in men following radical prostatectomy," AUA 2000, No. 705. Griffiths, G.J., "Exisulind Cell Pathways," Curr Opin Investig Drugs, 1(3), 386-91, 2000. Harper’s Biochemistry, 25th ed., Appleton & Lange, Stamford, CT, 2000. Lim, J.T., et al., "Sulindac derivatives inhibit growth and induce apoptosis in human prostate cancer cell lines," Biochem Pharmacol, 58(7), 1097-107, 1999. Piazza, G.A., et al., "Apoptosis primarily acounts 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 Res, 57(12), 2452-9, 1997. Pierson, A.S., et al., "A Phase 1 and pharmacologic (PK) study of exisulind (E) combined with Taxotere (T) in patients with advanced cancer," ASCO 2001, No. 475. Skopinska-Rozewska, E., et al., "Inhibition of angiogenesis by sulindac and its sulfone metabolite (FGN-1): a potential mechanism for their antineoplastic properties," Int J Tissue React, 20(3), 85-9, 1998. Soh, J.W. et al., "Cyclic GMP mediates apoptosis induced by sulindac derivatives via activation of c-Jun NH2-terminal kinase 1," Clin Cancer Res, 6(10), 4136-41, 2000. Van Stolk, R., et al., "Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis," Clin Cancer Res, 6(1), 78-89, 2000.
Evaluation by: Bob Benson and Howard Hansen Revised: 7/5/01. |
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