Seeking Clarity on the PSA Story


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I won’t redress the use of PSA, save to say that I’m glad my 3-decades-long mission against routine screening is beginning to see a flickering light at the end of the tunnel.

—Richard J. Ablin, PhD, DSc (Hon)

My feature interview in the August 15, 2012, issue of The ASCO Post, entitled “Rethinking the Role of PSA Screening in Public Health”1 drew swift reaction from well-known figures in the prostate cancer field. The subsequent Letters to the Editor, three in all, constituted a two-pronged attack. They first cast doubt on my discovery of prostate-specific antigen (PSA) in 1970, and then leveraged that doubt to question my widely publicized view that PSA screening in asymptomatic men does far more harm than good.

I have already responded to the first letter, by Drs. James Mohler and Donald Trump,2 in the September 15, 2012, issue of this publication.3 For the sake of concision and to avoid redundancy, I will collectively address the final two letters, from Drs. T. Ming Chu4 and William J. Catalona.5 However, given the fairly recent rethinking about PSA screening—notably reflected in the new guidelines from the American Urological Association (AUA)6—I won’t redress the use of PSA, save to say that I’m glad my 3-decades-long mission against routine screening is beginning to see a flickering light at the end of the tunnel.

Recapping the Discussion

The debate in brief: I discovered PSA in 1970, but the Chu and Catalona letters cited above argue that Dr. Chu, in 1979, was the true discoverer of PSA. As this is essentially a Roswell Park–centric feud, it is interesting to note that the late Dr. Gerald P. Murphy, former Director of the National Prostate Cancer Project and Roswell Park Memorial Institute (subsequently known as Roswell Park Cancer Institute) and coauthor with Dr. Chu on their 1979 paper, stated, “[W]e should not dwell on [when and by whom PSA was identified]. Rather, we should focus on the significance of the finding.”7

I could not agree more. Nonetheless, I’ll set the record straight once again, hopefully putting an end to this ongoing debate.

Different PSAs?

The common thread in the letters is that the PSA I discovered in 1970 is not the same as what Dr. Chu purified and characterized 9 years later. From a re-review of our results with three independent immunologists, it appears that this contention is rooted in biased interpretations of the two principal types of immunologic methods utilized, ie, precipitin and hemagglutinin assays.

Hemagglutinin studies—based on tanned cell hemagglutination and its inhibition—unequivocally demonstrated that PSA is present in human prostate extract, prostatic fluid, and seminal plasma. When viewed in context with precipitin data (gel-diffusion precipitation) for the reaction between antisera to human prostate extract and prostatic fluid, a very strong reaction of identity—designating a commonality of the content of each—was obtained. This showed that PSA was present in human prostate extract and prostatic fluid. In concert with subsequent studies by Wang et al,8 it was shown that PSA in seminal plasma originated from prostatic fluid.

In terms of biochemical and biophysical characteristics, I appreciate that Dr. Chu recognizes the limits of these techniques at the time of my team’s discovery. Nonetheless, my colleagues and I have subsequently been able to ascertain that the molecular weight of our PSA was in the range of 28 to 34 kDa (unpublished data). This molecular weight is commensurate with that subsequently established for PSA by Dr. Chu and others.

Other Points of Debate

Considering Dr. Chu’s dispute over my discovery, I question the motive and relevance of his statement, “Dr. Ablin has not published a new peer-reviewed paper on PSA since the early 1970s….” To the contrary, I published peer-reviewed manuscripts on PSA in 19979 and 2011.10 Quite frankly, other than commenting on the futility of PSA screening in several commentaries and editorials, there has been nothing “new” on the scientific front for me to write about.

On the subject of my 1979 communication with Dr. Chu referred to in his letter, other than inviting him to contribute a chapter on enzyme markers for prostate cancer to a book I edited,11 our exchanges were as follows: On March 16, I informed him that I noted his Federation Proceedings abstract of 1979, sent him reprints of our recent studies and suggested, given our mutual interest, that we consider collaborating. On October 2, I requested from him a reprint of Wang et al (Invest Urol, 17:159, 1979), inquired whether his nonprostatic acid phosphatase was identical to ours, and asked for a sample of his specific antigen and antiserum for comparison. On October 11, Dr. Chu replied, “We are not prepared yet to distribute our antigen preparation, as the supply is still limited. However, if you have your antigen purified and wish to exchange a small quantity with ours, we shall be pleased to do so.” Certainly, in concert with his just-published paper, this was somewhat of a mixed ­message.

With regard to Dr. Chu’s statement, “to date, Dr. Ablin has not made his PSA accessible to the scientific community,” I would say this: When I left the University of Buffalo for another position in mid-1970, my research materials (save for very small selected aliquots) remained there. In fact, other than Roswell Park’s furtive request in 1979 (referred to above), I do not recall other requests, which in any event I could not have fulfilled, given my lack of an adequate sample.

Contrary to Dr. Chu’s assertion, my comments referring to his 1977 Federation Proceedings abstract12 were not “criticisms.” They merely stated that the information reported in that abstract was incorrect. Certainly, in accord with Dr. Chu’s own remarks, “Readers should base their judgment … on science and evidence…,” That is exactly what I did. I believe, from a chronologic perspective, it is ironic that just when Doctor Chu was joining Roswell Park in 1970, I had already discovered PSA.

‘True’ History Reinterpreted

As for Dr. Catalona’s “true” history of the discovery of PSA, he has omitted reference to the 2005 AUA presentation by Rao et al,13 wherein the authors state, “It is … misinterpreted in the literature that Wang et al were the first to identify PSA in the human body taking the credit away from Dr. Richard Albin.”

And permit me to further direct attention to the 2007 paper by Kundu et al,14 on which Dr. Catalona was the corresponding author. The opening sentence in the Discussion section read, “Prostate-specific antigen was first identified in prostate tissue in 1970, purified in 1979, identified in serum in 1980,” [at which point the authors cited these three references: Ablin et al: J Reprod Fert 22:573, 1970; Wang et al: Invest Urol 17:159, 1979; and Papsidero et al: Cancer Res 40:2428, 1980].

Circling Back

On behalf of my earlier co-workers and the immunologists who kindly re-reviewed our initial studies, I do hope the foregoing account may provide further clarity and some degree of resolution to those who continue to question my discovery of PSA in 1970. Perhaps we all should pause in this continuing debate and remember the words of the late Dr. Murphy: “[W]e should not dwell on [when and by whom PSA was identified]. Rather, we should focus on the significance of the finding,”7 and, if I might add, its appropriate use. ■

 

—Richard J. Ablin, PhD, DSc (Hon)
Department of Pathology
University of Arizona College of Medicine
The Arizona Cancer Center and BIO5 Institute
Tucson, Arizona

References

1. Piana R: Rethinking the role of PSA screening in public health. ASCO Post 3(12):1, 10, 18, 2012.

2. Mohler J, Trump D: More thoughts on PSA (letter). ASCO Post 3(14):2, 2012.

3. Ablin RJ: Dr. Ablin’s reply (letter). ASCO Post 3(14):83, 2012.

4. Chu TM: Origins of PSA testing: The conversation continues (letter). ASCO Post 3(17):110, 2012.

5. Catalona WJ: The ‘true’ history of the discovery of prostate-specific antigen (letter). ASCO Post 3(18):95, 2012.

6. American Urological Association: Early Detection of Prostate Cancer: AUA Guideline. April 2013. Available at www.auanet.org. Accessed July 16, 2013.

7. Murphy GP: The Pannek/Partin article reviewed. Re: Prostate-specific antigen: What’s new in 1997. Oncology 11:1279-1280, 1997.

8. Wang MC, Loor RM, Li SL, et al: Physicochemical characterization of prostate antigen purified from human prostate gland and seminal plasma. IRCS Med Sci 11:327-328, 1983.

9. Ablin RJ: A retrospective and prospective overview of prostate-specific antigen. J Cancer Res Clin Oncol 123:583-594, 1997.

10. Haythorn MR, Ablin RJ: Prostate-specific antigen testing across the spectrum of prostate cancer. Biomark Med 5:515-526, 2011.

11. Ablin RJ (ed): Prostatic Cancer, p 321. New York, Marcel Dekker, 1981.

12. Wang MC, Valenzuela LA, Murphy GP, et al: Tissue specific and tumor specific antigens in human prostate. Fed Proc 36:1254, 1977.

13. Rao AR, Sharma M, Shergill I, et al: History of the discovery of prostate specific antigen: Unravelling the controversy. American Urological Association Annual Meeting. Abstract 892. Presented May 21-26 2005.

14. Kundu SD, Roehl KA, Yu X, et al: Prostate specific antigen density correlates with features of prostate cancer aggressiveness. J Urol 177:505-509, 2007.



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