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Commentary |
Chao Family Comprehensive Cancer Center, University of California, Irvine, California
Requests for reprints: Frank Meyskens Jr., UCI Cancer center Hematology/Oncology Bldg. 44, Route 81 101 city Drive cancer Center CA. Phone: 714-456-6310; Fax: 714-456-2240. E-mail: flmeyske{at}uci.edu
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The Spring Years: The Early Days |
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In the late 1970s, there was also a lot of interest in the differentiation effects of retinoids on leukemic cells. An interesting trial of high-dose vitamin A in patients with chronic myelogenous leukemia (Southwest Oncology Group 79-84) was started, and in 1994, the results were finally reported. A substantial increase in relapse-free and total survival was evident (12), but more targeted therapy was being developed that eventually led to Imatinib (Gleevec). Whether retinoids and Imatinib should be combined is probably worth pursuing at an investigational level as drug resistance seems to occur in many patients.
In a memorable Gordon conference in 1978, I met Michael Sporn. We had a lengthy conversation, and my interest in chemoprevention was sparked. At that time, the gynecologic group at the University of Arizona was very strong, leading to an interest in the potential prevention of cervical cancer. As we wished to avoid the systemic toxicity of retinoids, and concern about teratogenic effects was high, we decided to develop the retinoid ß-trans-retinoic acid and to deliver it topically to patients with cervical intraepithelial neoplasia. In series, pilot, pharmacokinetic, phase I and II studies were done and reported (13-15). The results of these investigations encouraged us to submit an NIH application to support a randomized trial; an ironic result of the review process was that the study section strongly suggested that the elegant markers we proposed be dropped. Of course, after the results of the phase III trial were published in 1994 (16), the most frequent question I received for the next few years was, "When are you going to report the biomarker studies?" Although the results of the phase III trial showed some activity in moderate cervical dysplasia (16), toxicity was not insignificant, and the use of topical retinoic acid in the clinical setting for cervical intraepithelial neoplasia is infrequent.
One final important area with which we were engaged was participation, as a clinical unit, in the CARET trial in which supplementation with retinol or ß-carotene was used to try to prevent lung cancer in heavy smokers. As is well known, both this study and the ATBC trial from Europe showed that ß-carotene increased rather than decreased lung cancers (17, 18). This was a shocking result that led me to take a sabbatical in a redox laboratory and has led to a whole new area of research, including reconsideration of the factors affecting the pathogenesis of cutaneous melanoma (19), returning full circle to where we had started in 1978 when retinoids had been explored as treatment modalities for melanoma (1).
This sojourn with retinoids and those trials in the early years (the 1980s) as well as the experiences of other investigators led to several important lessons:
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The Summer Years: Difluoromethylornithine and Bowman-Birk Inhibitor Concentrate |
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Nevertheless, a series of studies in animal models was done in the 1980s that suggested that difluoromethylornithine was an effective chemoprevention agent, particularly against colon cancer (23, 24). These observations led to a series of clinical chemoprevention studies in concert with my Arizona colleague Gene Gerner (25-27). For all these trials, patients who had had a prior colonic adenoma were our target population. The basic strategy was this: because we knew the highest dose at which the drug would be given in a therapeutic trial, we implemented a dose de-escalation design. In the initial 1-month trial, the goal was to achieve a dose that no longer modulated polyamines in rectal colonic mucosa (25). Based on these results, a 1-year trial using three doses of difluoromethylornithine and a placebo group was conducted in which the goal was to show polyamine modulation and no toxicity. An analysis of the results indicated that a dose of 200 mg/m2/d decreased polyamines, and that side effects in the difluoromethylornithine group were no greater than that seen in the placebo arm (26).
At that point, in about 1997, we were faced with a critical decision: How should we do the randomized phase III trial in which change in the number of colon adenomas would be the end point? Should the study be difluoromethylornithine alone versus placebo or should difluoromethylornithine be combined with another agent? If another drug, which? Most likely, a nonsteroidal anti-inflammatory drug. If a nonsteroidal anti-inflammatory drug, then nonspecific or specific? A lot of discussion ensued, and we elected to start a randomized phase IIb trial in which the combination of low-dose difluoromethylornithine and low-dose sulindac was the active arm. The end point was to be a comparison, between treatment and placebo, of the modulation of colonic polyamine and prostaglandin levels and other markers and recurrence and biology of adenomatous polyps. Accrual has been completed, and all patients passed their 3-year colonoscopy evaluation in October 2005; there are continuing discussions with the Data and Safety Monitoring Board as to whether to report this analysis because this study has been morphed into a larger phase III trial (see below).
In the middle of the phase IIb trial, we made the decision to use the study as a basis for a phase III interventional trial with a 2 x 2 factorial design (difluoromethylornithine, sulindac, difluoromethylornithine + sulindac, placebo); however, two unsuccessful attempts at funding led us to simplify the design (although markers were retained!) to a two-arm trial of difluoromethylornithine plus sulindac versus placebo. Accrual was 80% complete at the time of the first Data and Safety Monitoring Board review in February 2006; the recommendations were made that the study should continue, further accrual was not necessary, and long-term audiology testing was recommended. However, the Data and Safety Monitoring Board recommended that no results should be released at this time. Follow-up is continuing. Those interested in a detailed discussion of the development of polyamines, difluoromethylornithine, and chemoprevention are referred to ref. 28.
My interest in Bowman-Birk inhibitor was initiated by Dr. Ann Kennedy of the University of Pennsylvania at a conference on nutrients in 1988. Bowman-Birk inhibitor is a unique protein that was discovered in 1942; a large amount of preclinical data suggest substantial chemoprevention activity. Among its more prominent properties is that this protein remains intact after oral ingestion, inhibits a wide range of proteases, and has a chymotrypsin active site. The unique properties of this agent and the extensive activity of Bowman-Birk inhibitor in in vitro assays and in animal models are summarized in several reviews (29, 30); most relevant to this current discussion was the demonstration of activity in the hamster oral cheek pouch model in 1986 (31), and in 1992, the demonstration of mucosal proteases in exfoliated oral keratinocytes in humans (32). These data provided the basis for development of Bowman-Birk inhibitor as a drug, which was a formidable task. After an IND was obtained, a phase I trial was conducted (33), and subsequently, a 1-month phase IIa single arm dose-escalation study was completed (34, 35). The drug was well tolerated and produced a 32% complete plus partial response rate with a dose-response effect, and modulation of markers, such as the marker neu in serum and oral keratinocytes, were in the anticipated direction (34, 35). Based on these results, a phase IIb 6-month randomized trial was initiated in patients with oral leukoplakia. Eighty of the projected 140 patients have been accrued; four new sites, in different geographic areas, have been added as subject accrual has been exhausted in the initial sites. We anticipate completing this trial by 2008.
This odyssey over the past 17 years has led to several important realizations:
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The Autumn Years: New Thoughts and New Directions |
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There are many more issues that need to be explored, especially in the broader context of prevention and health maintenance. Recently, an update of IEN has begun to explore some of these issues (39), but much more needs to be discussed and explored, and a deep examination of the field needs to occur.
In the meantime, we are trying to continue our logical approach on two major fronts: new agents and new ideas. Within the next few months, we will be launching the following early-phase innovative trials:
-fetoprotein in patients with hepatitis C cirrhosis and moderately elevated -fetoprotein (T. Morgan, Protocol PI). In all these studies, extensive biomarkers will be measured.
Our other novel contribution involves an experimental and epidemiologic reexamination of the pathogenesis of human melanoma. The background for this adventure is discussed in ref. 40. We have done a large number of studies involving biophysical, chemical, and molecular approaches as well as reexamined the epidemiologic data (19, 41, 42). We have come to the following conclusion: the oxidation of melanin and its conversion from an antioxidant to pro-oxidant early in the pathogenic process of melanoma genesis is a key (? first) epigenetic event in the development of human melanoma. This observation has enormous implications for thinking about the etiology, prevention, and treatment of melanoma (19, 41).
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The Winter Years: Thinking about the Next Generation |
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I often have heard the late Ernst Wynder say, "The goal of medicine should be to help us to die young at an old age." Kurzweil argues that in 2050, we should be prepared to live forever as a biochip (see refs. 44, 45). Having just passed age 60 this year, I am not sure which option I would choose but I began writing poetry again a few years ago (46) after a long hiatus. I offer these visions.
CyborgI.
Vision focused by glass
Hearing amplified by audio
Breasts augmented by silicone
Hips, knees, wrists, ankles
...artificially constructed.
Hearts paced and voices synthesized
and now humungous organs for sale.
II.
At what level does the physical become biology
and of religious concern
when neural interfaces are already in place
that make stiff men walk.
Frank L. Meyskens, Jr.
Cherry Blossom Time
Nature renews.
Why not I?
It's as if the universe
is quantum Wu Li,
and I was Newtonian,
Or perhaps, on a good day, Einsteinian.
But on earth, Winter's bare limbs
become Spring's rapture
of white and pink.
and I just look more grey.
If the past is not permissible
and the future is always
a possibility, what does that
make today?
I guess it's the day
I noticed that I am no longer young.
Though my mind is twenty-five,
the body is no longer in sync.
Perhaps a personal trainer
will do the trick,
and I can learn to bloom again,
like a cherry blossom tree.
Frank L. Meyskens, Jr.
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Footnotes |
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Note: This report is a summary of a presentation given in Bethesda, Maryland on February 27, 2006 at the 30th annual meeting of the American Society of Preventive Oncology as the Distinguished Career Achievement Award Lecture. The entire power point lecture will be provided upon request as will the lecture given on "new thoughts on the pathogenesis of melanoma" mentioned in this report.
Received 7/21/06; accepted 7/24/06.
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References |
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-Difluoromethylornithine, a polyamine inhibitor: its potential role in controlling hair growth and in cancer treatment and chemo-prevention. Int J Dermatol 2006;45:337–44.[Medline]-difluoromethylornithine in patients with colon polyps. J Natl Cancer Inst 1994;86:1122–30.-Difluoromethylornithine on rectal mucosal levels for polyamines in a randomized, double-blinded trial for colon cancer prevention. J Natl Cancer Inst 1998;90:1212–8.-Difluoromethylornithine and polyamine levels in the human prostate: results of a phase IIa trial. J Natl Cancer Inst 2000;93:57–9.This article has been cited by other articles:
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  J. Yang, S. Zaja-Milatovic, Y.-M. Thu, F. Lee, R. Smykla, and A. Richmond Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy Mol. Cancer Ther., March 1, 2009; 8(3): 636 - 647. [Abstract] [Full Text] [PDF]
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