Indole-3-Carbinol as an Alternative to Interferon-alfa Therapy in Treatment of

Recurrent Respiratory Papillomatosis

by

Linda Garrelick

Overview

Recurrent respiratory papillomatosis (RRP) is a serious viral disease occurring in both children and adults. RRP is the most common benign tumor occurring in infants and children (Bauman and Smith, 1996) and is potentially fatal. In almost every case of RRP, the true and false vocal folds are the primary areas of papilloma growth (Coll et al., 1997) and a life-threatening blockage of the glottis is always a potential threat. In more aggressive forms of RRP, papilloma growth extends to the trachea, bronchi and, sometimes, the lungs.

Hoarseness is the "heralding symptom of RRP" (Bauman and Smith, 1996). As Kashima, Mounts and Shah (1996) note, tell-tale hoarseness is often apparent at the time of first vocalization in those infants afflicted with the disease . Other symptoms include a chronic cough, shortness of breath, stridor, a weak cry, and "paroxysms of choking" (Bauman and Smith, 1996).

Human papillomaviruses (HPV) 6 and 11 have been identified as the infectious agents in RRP (Quick et al. as cited in Bauman and Smith, 1996). It is now widely accepted that the disease is transmitted to infants pre- or perinatally by mothers infected with HPV in the form of genital condyloma. Because the incidence of RRP in infants (approximately 2,000 annually) is not consistent with the number of children delivered vaginally to mothers with maternal condyloma (Kashima et al., 1996), researchers believe that factors other than exposure to the virus lead to infection (Bauman and Smith, 1996). This belief is supported by data from one study in which 50% of infants born to HPV-infected mothers tested positive for HPV immediately after birth, but later showed no signs of HPV infection (Puranen et al. as cited in Bauman, 1996). Researchers have recently discovered a genetic defect in 75% of HPV patients with RRP which might be a predisposing factor for infection (Bauman et al., 1997).

Treatment of RRP is primarily surgical, with carbon dioxide laser being the current treatment of choice (Derkay, 1995). Laser treatment is preferable to other surgical methods because it allows for precise removal of warts and controls bleeding better than other methods such as cryosurgery and removal with forceps (Bauman and Smith, 1996). Results of a survey study published in 1995 indicated that 92% of the physicians surveyed chose to use laser surgery for papilloma excision rather than other surgical methods (Derkay, 1995). Unfortunately, surgery is only a temporary treatment for many patients because of the recurrent nature of the disease (Kashima et al., 1996). Some patients require surgical procedures as frequently as every week, and most others require surgery every 3 to 4 months in order to keep their airway open.

The recurrent nature of RRP is attributed to the fact that HPV genomes remain latent in seemingly normal tissue surrounding the excised papillomas, and seem to recur when activated by unknown mechanisms (Bauman and Smith, 1996 & Bent and Porubsky, 1993).

Because surgery is not a cure for RRP, researchers have looked to certain drugs as adjuncts to treatment with the hope of finding a therapy that will result in remission or, at least, extend the intervals between surgeries. Currently, interferon-alfa is the most widely-used adjuvant therapy for RRP (Derkay, 1995). Other adjuvant drug therapies include acyclovir, accutane, ribavirin, photodynamic therapy and indole-3-carbinol.

Purpose

To date, the literature does not indicate that any single drug is effective in treating all persons with RRP. For unknown reasons patients have different responses to adjuvant therapies. From the literature it is apparent that patients often have to try several different drugs before finding one that reduces the severity of disease. Keeping this in mind, it seems logical that physicians would begin with the most benign agent when initiating adjuvant therapy. However, this does not appear to be the case.

As mentioned previously, interferon is the most-prescribed adjuvant for RRP treatment. It is not, however, the least harmful drug that can be used to treat RRP nor is it necessarily the most effective drug. Among the alternative adjuvant therapies currently in use, indole-3-carbinol appears to have similar efficacy to interferon and is probably one of the least harmful drugs that can be used to control RRP. The purpose of this paper is three-fold: (i) to present efficacy data from interferon and indole-3-carbinol research, (ii) to suggest that there is an explanation, which has not yet been explored by researchers, for the effects of interferon on RRP, and (iii) in light of this possible explanation for the effect of interferon on RRP, to propose that indole-3-carbinol take the place of interferon as the most widely-utilized adjuvant drug in current treatment for RRP.

Efficacy of Interferon-alfa and Indole-3-carbinol in treating RRP

Interferon-alfa (“IFN”) is a group of proteins with antiviral, antiproliferative and immunomodulatory properties (Crockett et al, 1987). Once produced from human lymphoblastoid cells, interferon alfa is now manufactured by means of recombinant DNA techniques (Bauman and Smith, 1996). IFN is an anti-viral agent against viruses which proliferate by RNA replication (Wolff, 1997), but the exact way in which IFN prevents viral RNA replication is unknown. The mechanisms behind the antiproliferative and immunomodulatory effects of interferon alfa are also little-understood (Crockett et al, 1987).

The first results of research regarding interferon-alfa and its effect on RRP were published in 1981, by a group of Swedish scientists. At the time of their research, a viral etiology was suspected, but not proven, for RRP (Lundquist et al., 1984). Because of interferon's antiviral properties, they postulated that treatment with the drug could be effective against RRP. (Lundquist et al., 1984). Their initial findings supported the use of IFN in RRP treatment and led to further research.

Some of these same researchers (Lundquist, Haglund, Carlsoo, Strander and Lundgren) did a subsequent study of the effects of interferon alfa on RRP, the results of which were reported in 1984. They found that, of 17 patients treated, 13 (76%) had a complete response (nine patients being "cured" [1]), 3 patients (18%) had a partial response, and one (6%) had no response. Recurrence of papilloma growth occurred in 8 of the 17 patients, including some who had had a complete response.

Other studies followed the Swedish studies and supported the findings of the pilot researchers:

In 1987, Lusk and McCabe reported from their study in which patients treated with IFN for one year were followed for a period of 3 years after treatment. They found that 5 of 16 patients (29%) were disease-free for at least some period after treatment, while nine (53%) had a partial response to IFN. Two patients (18%) had no response to IFN. Five patients suffered recurrence of disease when treatment was stopped, indicating that they remained asymptomatic only while using IFN.

In 1991, Leventhal, Kashima, Mounts, Thurmond, Chapman, Buckley, Wold and the Papilloma Study Group published their research findings regarding long-term response to IFN treatment. Their data showed that, of 60 patients, 22 (37%) had complete responses, 25 (41%) had partial responses, and 13 (22%) had no response. As in the study of Lundquist et al., several patients (5) experienced recurrence of papilloma growth when IFN treatment was halted.

In 1995, Avidano and Singleton published their findings regarding IFN treatment. Of 24 pediatric patients, 13 (54%) had a complete response, 8 (33%) had a partial response and 3 (12%) had no response. Avidano and Singleton claim to have had a durable response to IFN therapy when IFN treatment is withdrawn.

Bauman and Smith (1996) summarize findings of interferon therapy research (including much of the research described above), stating that IFN "induces complete resolution of clinical disease in approximately 30% to 50% of patients and partial resolution in 20% to 42%".

In spite of agreement on the fact that IFN can effect a positive response in RRP treatment, researchers do not agree on one crucial aspect of interferon therapy: duration of the response to IFN therapy (Lippman et al., 1994)). Several studies, including some of those listed above, indicate that recurrence of papilloma growth is a problem when treatment is withdrawn. Avidano and Singleton attribute such recurrence to “the lower dosing regimen and the source of the IFN (1995, p. 200) in previous studies. Still, the issue remains to be resolved and it is possible that, when withdrawn, the effects of IFN upon RRP are nullified. The implication, then, is that patients might have to undergo long-term treatment with IFN in order to see a lasting improvement in their condition.

Indole-3-carbinol (I3C) is a chemical found in cruciferous vegetables (Coll et al., 1997) which has been found to have beneficial effects for RRP therapy. In recent years, research has determined an anti-tumorgenic role for I3C in the way in which it affects metabolism of the estrogen, estradiol (Newfield et al., 1993). Following is a description of how the role of I3C in estradiol metabolism can affect the course of RRP:

Estradiol metabolizes into either 16a-hydroxyestrone (16a-OHE1) or 2-hydroxyestrone (2-OHE1). 16a-OHE1 has been found to have tumor-proliferating properties, while 2-OHE1 has been found to reduce tumor growth (Newfield et al., 1993). When estradiol metabolism into either of these substances is increased, an accompanying decrease in the formation of the other substance occurs (Newfield et al, 1993). In other words, when 16a-OHE1 formation increases, there is a concomitant decrease in 2-OHE1 formation (and vice versa) (Coll et al., 1997). Researchers have found that administration of I3C has a modulating effect on estradiol metabolism. Specifically, I3C appears to increase the ratio of 2-OHE1 to 16a-OHE1 formation.

The implications of findings regarding the effect of I3C on estradiol metabolism are very relevant to research for HPV treatment. Laryngeal tissue has been found to be extremely hormone-sensitive. In fact, Newfield et al. (1993) found that normal laryngeal tissue metabolizes estradiol into 16a-OHE1 (the tumorgenic metabolite) at high levels, and that such metabolism is even higher in HPV-infected laryngeal tissue.

Because of the 2-OHE1-increasing (and accompanying 16a-OHE1decreasing) effect of I3C on estradiol metabolism, Newfield et al. (1993) studied the effects of I3C on cultured laryngeal tissue (which is high in 16a-OHE1, as previously noted). They found that I3C "abrogated the proliferative effects of estradiol on laryngeal cells in culture". In addition, the researchers found that mice grafted with HPV-infected laryngeal tissue, when given I3C in dietary form (specifically, dried cabbage), had a decreased development of papillomas as compared to mice who had not been given I3C (Newfield et al., 1993).

Currently, the only research that has been published regarding I3C therapy and RRP is a case study by Coll et al.(1997), in which aggressive RRP in a 25-month old child was controlled to the point of remission by dietary supplementation with I3C in the form of cabbage juice. Preliminary reports of a clinical trial indicate that, of 11 patients, 6 (55%) had a complete response to I3C, 1 ((9%) patient had a partial response and 4 patients (36%) had no response (Rosen, 1996). Responses to an adjuvant therapy survey conducted by the RRP Foundation have provided the following data: of 55 users of I3C, 11 (20%) had a complete response, 21 (38%) had a partial response and 24 (44%) had no response (Stern, 1997). Further studies of I3C are currently taking place and more are planned.

I3C is currently available in capsule form as a dietary supplement, but has not yet received FDA approval. As noted in the description of the case study, one patient experienced results by drinking large amounts of cabbage juice (which naturally contains significant amounts of I3C) on a daily basis. Thus, it may not be necessary to take the supplement if dietary sources of I3C are found to be successful.

Discussion

Interestingly, when compared, the efficacy of IFN and I3C , as reported in the research above, are relatively similar. The similarity of efficacy results for IFN and I3C in the treatment of RRP would not be so interesting were it not for an obscure finding regarding IFN: IFN has been found to reduce serum estradiol levels in women (Kauppila et al., 1982). Is it possible, then, that IFN acts against RRP by decreasing estradiol levels (in a way similar to that in which I3C has an antiproliferative effect)?

In answering this question, the history of IFN therapy for RRP must be considered. The researchers who first applied IFN to RRP therapy selected IFN almost arbitrarily: because it was suspected that a viral agent was responsible for RRP, these researchers decided to try IFN, which had been shown to have “antiviral effects" (Lundquist et al., 1984). At this point in time (late 1970's), researchers had not yet discovered that HPV -- a DNA virus -- (Wolff, 1997) was responsible for RRP. Because the research met with some success, further studies of IFN as an adjuvant therapy for RRP took place and confirmed that IFN is effective in treating some cases of RRP.

It is also interesting that no one has specifically addressed the way in which IFN works in treating RRP. Researchers seem to attribute the efficacy of IFN primarily to its antiviral effects, rather than its antineoplastic or immunomodulatory properties (Avidano and Singleton, 1995). However, IFN is an antiviral agent against RNA, not DNA -- and HPV is a DNA virus. The fact that IFN works against RNA viruses and not DNA viruses might explain why the HPV genome remains latent in normal-appearing laryngeal tissue, even after IFN treatment. Perhaps it is not, after all, IFN's antiviral properties that operate against papilloma growth.

If it is true that IFN's antiviral effects are not responsible for the improvements seen in RRP with IFN therapy, a possible explanation might be that the antiproliferative effects of IFN, which are poorly understood, are responsible. If, as some researchers have found, estradiol levels are decreased in patients when they undergo IFN therapy (Kauppila et al., 1982), perhaps it is by reducing estradiol levels that IFN works against RRP. If estradiol has a tumorgenic effect (Newfield et al., 1993) then it is possible that reduction in levels of estradiol has an antiproliferative effect. Finally, if estradiol reduction is the mechanism behind the success of IFN in RRP treatment, then IFN might operate in much the same way as I3C (which boosts formation of antiproliferative estradiol metabolites and decreases the formation of tumorgenic estradiol metabolites). Further research regarding (i) the effect of IFN therapy on estradiol production and (ii) the effect of decreased levels of estradiol (versus decreased levels of estradiol metabolites) on RRP appears to be warranted. Findings of such research might indicate that I3C could take the place of IFN as the primary adjuvant drug in treatment of RRP.

The replacement of IFN with I3C as the first choice in adjuvant drug therapies for RRP, especially in the treatment of children, is desirable for several reasons. First, serious side effects and toxic effects have been associated with IFN. These effects include fever, hair loss, fatigue, growth retardation in children, liver toxicity, confusion, depression, neurologic symptoms and immunologic reactions (Crockett et al., 1987). Despite the severity of some of these side effects, Crockett et al. (1987) believe that these effects are “tolerable, controllable and reversibleble" and that treatment of RRP should continue to include IFN. Considering that children comprise a large percentage of RRP sufferers, these effects of IFN do not seem acceptable given that a more benign alternative treatment is available.

I3C has not been found to have any side effects other than mild stomach upset in some users (Stern, 1997).

Patient compliance is another factor favoring I3C. The side effects of IFN, as well as the fact that IFN is administered via injection, likely have a negative effect on patient compliance. In fact, some researchers indicated compliance problems with some of their patients (Lundquist et al., 1984 & Lusk et al., 1987). On the other hand, compliance is less likely to be a problem with I3C therapy. I3C is taken as a capsule or powder, is easy to use and, because it is chemically identical to a natural compound derived from cruciferous vegetables, more attractive to parents as a treatment for children.

Cost is also an issue. Interferon therapy for children with RRP can cost over $3,000 annually at the dosages recommended by researchers (Mosby's Complete Drug Reference, 1997 & Avidano and Singleton, 1995). I3C treatment for children, on the other hand, would cost less than $600 annually (based on Fall 97 pricing from Theranaturals, Inc.).

Given the factors addressed above, when it is considered that patients might have to remain on an adjuvant therapy for a long period of time to sustain a durable response, the choice of I3C seems to be particularly preferable to IFN.

Summary

Interferon and indole-3-carbinol are two drug therapies currently in use to treat recurrent respiratory papillomatosis. Studies suggest that these therapies have relatively similar efficacy rates. In addition, there is the possibility that these two therapies have the same effect on RRP due to their effect on estradiol. When the issues of side effects, patient compliance and cost are considered, I3C appears to be much more attractive than IFN as a treatment for RRP. If research could determine that I3C and IFN have similar functions in treating RRP, perhaps I3C would take the place of IFN as the most-prescribed treatment for RRP and fewer people would have to suffer from the high cost and the unpleasant side effects of interferon therapy.

References

Avidano, M.A. and Singleton, G.T. (1995) Adjuvant drug strategies in treatment of recurrent respiratory papillomatosis. Otolaryngology - Head and Neck Surgery, 112, 197-202.

Bauman, N., Smith, R. & Burke, D. (1997, Spring). HLA Typing in Pediatric Patients with RRP. Recurrent Respiratory Papillomatosis Newsletter, Vol. 6,Number 1, 7.

Bauman, N.M. and Smith, R.J.H. (1996). Recurrent respiratory papillomatosis. Pediatric Clinics of North America, 43, 1385-1401.

Bent, III, J.P., and Porubsky, E.S. (1993). Recurrent respiratory papillomatosis. Insights in Otolaryngology, Volume 8, Number 3, 3-8.

Coll, D.A., Rosen, C.A., Auborn, K., Potsic, W.P. & Bradlow, H.L. (1997). Treatment of recurrent respiratory papillomatosis with indole-3-carbinol. American Journal of Otolaryngology, 18, 283-285.

Crockett, D.M., McCabe, B.F., Lusk, R.P. & Mixon, J.H. (1987). Side effects and toxicity of interferon in the treatment of recurrent respiratory papillomatosis. Annals of Otology Rhinology Laryngology, 96, 601-606.

Derkay, C.S. (1995). Task force on recurrent respiratory papillomas: a preliminary report. Archives of Otolaryngology Head & Neck Surgery, 121, 1386-1391.

Kashima, H.K., Mounts, P. & Shah, K. (1996). Recurrent respiratory papillomatosis. Obstetrics and Gynecology Clinics of North America, 23, 699-705.

Kauppila, A., Cantell, K. Janne, O., Kokko, E. & Vikho, R. (1982). Serum sex steroid and peptide hormone concentrations, and endometrial estrogen and progestin receptor levels during administration of human leukocyte interferon. [On-line]. International Journal of Cancer, 15, 291-294. Abstract from: Internet GratefulMed File: Medline Item: 82166484

Leventhal, B.G., Kashima, H.K., Mounts, P., Thurmond, L., Chapman, S., Buckley, S., Wold, D. & the Papilloma Study Group. (1991). Long-term response of recurrent respiratory papillomatosis to treatment with lymphoblastoid interferon alfa-n1. New England Journal of Medicine, 325, 613-617.

Lippman, S.M., Donovan, D.T., Frankenthaler, R.A., Weber, R.S., Earley, C.L., Hong, W.K. & Goepfert, H. (1994). 13-cis-retinoic acid plus interferon-a2a in recurrent respiratory papillomatosis. Journal of the National Cancer Institute, 86, 859-861.

Lundquist, P.G., Haglund, S., Carlsoo, B., Strander, H. & Lundgren, E. (1984). Interferon therapy in juvenile laryngeal papillomatosis. Otolaryngology - Head and Neck Surgery, 92, 386-391.

Lusk, R.P., McCabe, B.F. & Mixon, J.H. (1987). Three-year experience of treating recurrent respiratory papilloma with interferon. 24Annals of Otology Rhinology Laryngology, 96, 158-161.

Mosby's Complete Drug Reference 1997 Physicians Gen Rx, 7th Ed. (1997). St. Louis:Mosby-Year Book, Inc.

Newfield, L., Goldsmith, A., Bradlow, H.L. & Auborn, K. (1993). Estrogen metabolism and human papillomavirus-induced tumors of the larynx: chemo-prophylaxis with indole-3-carbinol. Anticancer Research, 13, 337-342.

Puranen, M., Yliskoski, M., Syrjanen, K., et al. (1996). Vertical transmission of human papillomavirus (HPV) from infected mothers to their newborn babies and persistence of the virus in the childhood. Am J Obstet Gynecol 174(2), 694-699.

Quick, C.A., Watts, S.L., Krzyzek, R.A., et al. (1980). relationship between condylomata and laryngeal papillomata. Annals of Otology Rhinology and Laryngology, 89, 467

Rosen, C. (1996, Spring). Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Recurrent Respiratory Papillomatosis Newsletter, Vol. 5,Number 1, 4.

Stern, W. (1997, Spring). Adjuvant therapy survey update. Recurrent Respiratory Papillomatosis Newsletter,Vol. 6, Number 1, 5.

Wolff, M.E.,(Ed.) (1997). Burger's Medicinal Chemistry and Drug Discovery, 4, 494-495. New York:John Wiley & Sons, Inc.

Wolff, M.E., (Ed.) (1997). Burger's Medicinal Chemistry and Drug Discovery, 5, 577-578. New York:John Wiley & Sons, Inc.


Footnotes

[1] A "cure" is questionable. Most researchers report that there is no such thing as a cure for RRP, as the HPV genome remains latent in normal-appearing laryngeal tissue (Bauman and Smith, 1996). At the time of this study, the exact viral etiology had yet to be determined, so these researchers would not have known to look for latent HPV in the laryngeal tissue of their "cured" patients.