how does tamoxifen interact with chemotherapy?

2
439 Mechanism of action of FK 506 and cyclosporin SIR,-The mechanism of action of FK 506 and cyclosporin is still unclear, as discussed by Dr Macleod and Dr Thomson (Jan 5, p 25). Both FK 506 and cyclosporin bind to immunophilins, proteins with peptidyl-prolyl cis-trans isomerase activity (PPIase), not phosphatidyl-prolyl isomerase, as erroneously stated by Macleod and Thomson. PPIase activity is inhibited by these drugs in vitro, but it is unknown whether PPIase has a physiological function and thus whether inhibition of this enzyme is important in immunosuppression. PPIase accelerates otherwise slow, rate-limiting isomerisation steps in the in-vitro folding of proteins to their fmal conformation. We have studied the folding of procollagen in suspended chick embryo tendon fibroblasts,’ a system that allows monitoring of protein folding in intact cells. We have shown that procollagen folding is slowed by cyclosporin, in both chick embryos and cultured human fibroblasts.’ Besides indicating that PPIase has a function in living cells, these findings suggest that PPIase inhibition may be crucial for immunosuppression and support the hypothesis2 that cyclosporin, and probably also FK 506, inhibit the folding of an unidentified protein that is critical to T-lymphocyte activation. Division of Metabolism, Department of Paediatrics, University of Zurich, 8032 Zurich, Switzerland BEAT STEINMANN ANDREA SUPERTI-FURGA Department of Biochemistry, Swiss Federal Institute of Technology, Zurich PETER BRUCKNER 1 Steinmann B, Bruckner P, Superti-Furga A. Cyclosporin A slows collagen triple-helix formation m vivo-indirect evidence for a physiologic role of peptidyl-prolyl cis-trans isomerase. J Biol Chem 1991; 266: 1299-303. 2. Kahan BD. Cyclosporine. N Engl J Med 1989, 321: 1725-38. Genital carcinomas in psoriasis patients treated with photochemotherapy SIR,-Dr Perkins and colleagues (Nov 17, p 1248) report from Glasgow 3 male patients with psoriasis from a cohort of only 130 patients in whom genital malignant disease had developed after fairly high doses of photochemotherapy (PUVA). Stern et all showed an alarming increased risk of genital tumours in PUVA- treated men, with an incidence of invasive squamous cell carcinoma 286 times that of the general population in those exposed to high-dose PUVA. A US multicentre study noted a significant overall increased cancer risk in PUVA patients 5--10 years after their first treatment,’ but European epidemiological surveys uniformly found an increased risk only in patients previously treated with other potential carcinogens and failed to reveal any direct correlation between increased risk and PUV A. 3-8 This discrepancy has so far not been explained, but it has been. suggested that the disparity in cancer risk between the US and European surveys could be attributable to differences in the therapeutic strategies used.9 Although a long-term follow-up study of about 3000 patients with psoriasis in the European multicentre PUVA studyl&deg; is continuing, the striking increase in risk of genital tumours reported by Stern_ 1 and by Perkins et al prompted us to look at the prevalence of genital tumours in male patients in continental Europe. A total of 32 599 patients have been treated in eleven European University centres in the past 13-16 years with systemic and topical (bath) PUVA. About 10-15% of these patients have received intermittent PUVA over 15 years. The highest cumulative UVA doses ranged from 1698 to 5580 J/cm. No genital tumours were observed in any of these patients. Although this analysis is uncontrolled and has not been tested statistically, the absence of genital tumours is remarkable. In view of the large number of patients and the risk of genital tumours postulated by Stern et al,9 we would expect to have found at least a few patients with such lesions. None of the American patients had had concomitant or previous herpesvirus infections but all had been treated, as had Perkins and colleagues’ Scottish patients, with tar and shortwave ultraviolet radiation before PUVA was initiated. However, Perkins et al feel that tar alone is not an additional risk factor; they ascribe the higher risk to the fact that their patients mostly have skin type 2 and thus are much more susceptible to ultraviolet-induced carcinogenesis than are central European patients. We would point out that our survey encompasses a considerable number of patients (39%) from Scandinavia who are also of skin types 1 and 2. We cannot explain the apparent discrepancy in tumour risk of continental European vs American and Scottish patients, apart from photobiological evidence that the American PUVA regimen is more carcinogenic than the European procedure. With respect to penile carcinomas it is noteworthy that in the USA many more men are circumcised than are in continental Europe, which would place these individuals in a higher risk group. Department of Dermatology I, University of Vienna Medical School, A-1090 Vienna, Austria K. WOLFF H. H&Ouml;NIGSMANN 1 Stem RS and Members of the Photochemotherapy Follow-up Study. Genital rumours among men with psoriasis exposed to psoralens and ultraviolet A (PUVA) radiation and ultraviolet B radiation. N Engl J Med 1990; 322: 1093-97. 2. Stem RS, Lange R. Photochemotherapy: follow-up study. J Invest Dermatol 1988; 91: 120-24. 3 Honigsmann H, Wolff K, Gschnait F, et al. Keratoses and non melanoma skin tumours in long-term photochemotherapy (PUVA). J Am Acad Dermatol 1980; 3: 406-14. 4. Lassus A, Reunala T, Idanpaan-Heikkila J, et al. PUVA treatment and skin cancer: a follow-up study. Acta Derm Venereol 1981; 61: 141-45. 5 Ros AM, Wennersten G, Lagerholm B. Long-term photochemotherapy for psonasis: a histopathological and clinical follow-up study with special emphasis on tumour incidence and behaviour of pigmented lesions. Acta Derm Venereol 1983; 63: 215-21. 6. Lindskov R. Skin carcinomas and treatment with photochemotherapy (PUVA). Acta Derm Venereol 1983; 63: 223-26. 7. Tanew A, Honigsmann H, Ortel B, et al. Nonmelanoma skin tumours in long-term photochemotherapy treatment of psoriasis. J Am Acad Dermatol 1986; 15: 980-85. 8 Henseler T, Christophers E, Honigsmann H, et al. Skin tumours in the European PUVA study. J Am Acad Dermatol 1987; 16: 108-16. 9. Gibbs NK, Honigsmann H, Young AR. PUVA treatment strategies and cancer risk. Lancet 1986; i: 150-51. 10. Henseler T, Wolff K, H&ouml;nigsmann H, et al. Oral 8-methoxypsoralen photochemotherapy of psoriasis. Lancet 1981; i: 853-57. How does tamoxifen interact with chemotherapy? SiR,&mdash;The Early Breast Cancer Trialists’ Collaborative Group has recently published a systematic overview of randomised trials of tamoxifen that began before 1985, concentrating on follow-up during the first five years.1 The results contain interesting data on a possible interaction of tamoxifen with chemotherapy. The trials were of two types-tamoxifen versus nil ("T alone trials") or tamoxifen plus chemotherapy compared with the same chemotherapy alone ("T plus C trials"). There is no evidence of a difference in the effect of tamoxifen in the two types of trial when the results are considered as a whole. However, the results can be divided into four categories on the basis of trial type-namely, with or without chemotherapy and age below 50 or 50 or more. When the endpoints of both mortality and recurrence (or prior death) are examined the magnitude of the odds reductions (and SD) favouring the tamoxifen-treated patients differs only in the T plus C, age less than 50 group: Mortality Recurrence Trial type Age < 50 Age 3 50 Age < 50 Age 50 T only 21(14)% 19(4)% 32(10)% 32(3)% T plus C -9 (9)% 22(6)% 8 (7)% 35(5)% Two arguments that this is not a real effect are that comparisons of odds reductions from different trials are not randomised and may be biased by patient selection, and that subgroup analyses such as this can easily generate spurious results. Statistically, this is a second-order interaction, and may therefore be difficult to believe. (The differential effect of tamoxifen in the < 50 and 50 age groups is first order. The suggestion that within this interaction there is also a difference in the effect dependent on whether or not chemotherapy is given is therefore second-order.) The plausibility of this effect is strengthened, however, by the fact that it appears for both the mortality and recurrence endpoints. Despite these reservations, we believe that the apparent reduction in the effect of tamoxifen in the presence of chemotherapy in patients less than 50 is

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Page 1: How does tamoxifen interact with chemotherapy?

439

Mechanism of action of FK 506 andcyclosporin

SIR,-The mechanism of action of FK 506 and cyclosporin is stillunclear, as discussed by Dr Macleod and Dr Thomson (Jan 5, p 25).Both FK 506 and cyclosporin bind to immunophilins, proteins withpeptidyl-prolyl cis-trans isomerase activity (PPIase), not

phosphatidyl-prolyl isomerase, as erroneously stated by Macleodand Thomson. PPIase activity is inhibited by these drugs in vitro,but it is unknown whether PPIase has a physiological function andthus whether inhibition of this enzyme is important in

immunosuppression.PPIase accelerates otherwise slow, rate-limiting isomerisation

steps in the in-vitro folding of proteins to their fmal conformation.We have studied the folding of procollagen in suspended chickembryo tendon fibroblasts,’ a system that allows monitoring ofprotein folding in intact cells. We have shown that procollagenfolding is slowed by cyclosporin, in both chick embryos andcultured human fibroblasts.’ Besides indicating that PPIase has afunction in living cells, these findings suggest that PPIase inhibitionmay be crucial for immunosuppression and support the hypothesis2that cyclosporin, and probably also FK 506, inhibit the folding of anunidentified protein that is critical to T-lymphocyte activation.

Division of Metabolism,Department of Paediatrics,University of Zurich,8032 Zurich, Switzerland

BEAT STEINMANN

ANDREA SUPERTI-FURGA

Department of Biochemistry,Swiss Federal Institute of Technology,Zurich PETER BRUCKNER

1 Steinmann B, Bruckner P, Superti-Furga A. Cyclosporin A slows collagen triple-helixformation m vivo-indirect evidence for a physiologic role of peptidyl-prolylcis-trans isomerase. J Biol Chem 1991; 266: 1299-303.

2. Kahan BD. Cyclosporine. N Engl J Med 1989, 321: 1725-38.

Genital carcinomas in psoriasis patientstreated with photochemotherapy

SIR,-Dr Perkins and colleagues (Nov 17, p 1248) report fromGlasgow 3 male patients with psoriasis from a cohort of only 130patients in whom genital malignant disease had developed afterfairly high doses of photochemotherapy (PUVA). Stern et allshowed an alarming increased risk of genital tumours in PUVA-treated men, with an incidence of invasive squamous cell carcinoma286 times that of the general population in those exposed tohigh-dose PUVA. A US multicentre study noted a significantoverall increased cancer risk in PUVA patients 5--10 years after theirfirst treatment,’ but European epidemiological surveys uniformlyfound an increased risk only in patients previously treated withother potential carcinogens and failed to reveal any directcorrelation between increased risk and PUV A. 3-8 This discrepancyhas so far not been explained, but it has been. suggested that thedisparity in cancer risk between the US and European surveyscould be attributable to differences in the therapeutic strategiesused.9

Although a long-term follow-up study of about 3000 patientswith psoriasis in the European multicentre PUVA studyl&deg; is

continuing, the striking increase in risk of genital tumours reportedby Stern_ 1 and by Perkins et al prompted us to look at the prevalenceof genital tumours in male patients in continental Europe.A total of 32 599 patients have been treated in eleven European

University centres in the past 13-16 years with systemic and topical(bath) PUVA. About 10-15% of these patients have receivedintermittent PUVA over 15 years. The highest cumulative UVAdoses ranged from 1698 to 5580 J/cm. No genital tumours wereobserved in any of these patients.Although this analysis is uncontrolled and has not been tested

statistically, the absence of genital tumours is remarkable. In view ofthe large number of patients and the risk of genital tumourspostulated by Stern et al,9 we would expect to have found at least afew patients with such lesions. None of the American patients hadhad concomitant or previous herpesvirus infections but all had beentreated, as had Perkins and colleagues’ Scottish patients, with tarand shortwave ultraviolet radiation before PUVA was initiated.

However, Perkins et al feel that tar alone is not an additional riskfactor; they ascribe the higher risk to the fact that their patientsmostly have skin type 2 and thus are much more susceptible toultraviolet-induced carcinogenesis than are central Europeanpatients. We would point out that our survey encompasses aconsiderable number of patients (39%) from Scandinavia who arealso of skin types 1 and 2.We cannot explain the apparent discrepancy in tumour risk of

continental European vs American and Scottish patients, apart fromphotobiological evidence that the American PUVA regimen is morecarcinogenic than the European procedure. With respect to penilecarcinomas it is noteworthy that in the USA many more men arecircumcised than are in continental Europe, which would placethese individuals in a higher risk group.

Department of Dermatology I,University of Vienna Medical School,A-1090 Vienna, Austria

K. WOLFF

H. H&Ouml;NIGSMANN

1 Stem RS and Members of the Photochemotherapy Follow-up Study. Genital

rumours among men with psoriasis exposed to psoralens and ultraviolet A (PUVA)radiation and ultraviolet B radiation. N Engl J Med 1990; 322: 1093-97.

2. Stem RS, Lange R. Photochemotherapy: follow-up study. J Invest Dermatol 1988; 91:120-24.

3 Honigsmann H, Wolff K, Gschnait F, et al. Keratoses and non melanoma skintumours in long-term photochemotherapy (PUVA). J Am Acad Dermatol 1980; 3:406-14.

4. Lassus A, Reunala T, Idanpaan-Heikkila J, et al. PUVA treatment and skin cancer: afollow-up study. Acta Derm Venereol 1981; 61: 141-45.

5 Ros AM, Wennersten G, Lagerholm B. Long-term photochemotherapy for psonasis:a histopathological and clinical follow-up study with special emphasis on tumourincidence and behaviour of pigmented lesions. Acta Derm Venereol 1983; 63:215-21.

6. Lindskov R. Skin carcinomas and treatment with photochemotherapy (PUVA). ActaDerm Venereol 1983; 63: 223-26.

7. Tanew A, Honigsmann H, Ortel B, et al. Nonmelanoma skin tumours in long-termphotochemotherapy treatment of psoriasis. J Am Acad Dermatol 1986; 15: 980-85.

8 Henseler T, Christophers E, Honigsmann H, et al. Skin tumours in the EuropeanPUVA study. J Am Acad Dermatol 1987; 16: 108-16.

9. Gibbs NK, Honigsmann H, Young AR. PUVA treatment strategies and cancer risk.Lancet 1986; i: 150-51.

10. Henseler T, Wolff K, H&ouml;nigsmann H, et al. Oral 8-methoxypsoralenphotochemotherapy of psoriasis. Lancet 1981; i: 853-57.

How does tamoxifen interact withchemotherapy?

SiR,&mdash;The Early Breast Cancer Trialists’ Collaborative Grouphas recently published a systematic overview of randomised trials oftamoxifen that began before 1985, concentrating on follow-upduring the first five years.1 The results contain interesting data on apossible interaction of tamoxifen with chemotherapy. The trialswere of two types-tamoxifen versus nil ("T alone trials") ortamoxifen plus chemotherapy compared with the same

chemotherapy alone ("T plus C trials").There is no evidence of a difference in the effect of tamoxifen in

the two types of trial when the results are considered as a whole.

However, the results can be divided into four categories on the basisof trial type-namely, with or without chemotherapy and age below50 or 50 or more. When the endpoints of both mortality andrecurrence (or prior death) are examined the magnitude of the oddsreductions (and SD) favouring the tamoxifen-treated patientsdiffers only in the T plus C, age less than 50 group:

Mortality RecurrenceTrial type Age < 50 Age 3 50 Age < 50 Age 50

T only 21(14)% 19(4)% 32(10)% 32(3)%T plus C -9 (9)% 22(6)% 8 (7)% 35(5)%Two arguments that this is not a real effect are that comparisons

of odds reductions from different trials are not randomised and maybe biased by patient selection, and that subgroup analyses such asthis can easily generate spurious results. Statistically, this is asecond-order interaction, and may therefore be difficult to believe.(The differential effect of tamoxifen in the < 50 and 50 agegroups is first order. The suggestion that within this interactionthere is also a difference in the effect dependent on whether or notchemotherapy is given is therefore second-order.) The plausibilityof this effect is strengthened, however, by the fact that it appears forboth the mortality and recurrence endpoints. Despite these

reservations, we believe that the apparent reduction in the effect oftamoxifen in the presence of chemotherapy in patients less than 50 is

Page 2: How does tamoxifen interact with chemotherapy?

440

not an artifact. We would like to offer supporting evidence from thesame overview.

Since cytotoxic chemotherapy frequently causes loss of

menstruation, which reflects a reduction in ovarian activity, muchof the beneficial effect of chemotherapy may be due to oestrogen-deprivation. If tamoxifen acts by antagonising oestrogenstimulation of breast cancer growth, it might not be expected to havean additive benefit when combined with chemotherapy sincemaximum benefit from the endocrine-sensitive component mayhave already been obtained through the cytotoxic chemotherapy.However, the reduced effect of tamoxifen in the presence ofchemotherapy in patients less than 50 may also be partly or whollydue to the association of age and oestrogen receptor (ER) status,since a greater proportion of young patients have ER-negativetumours.

Since tamoxifen also has several ER-independent effects, its lackof effect when given with chemotherapy to younger women couldbe due to inhibition of ER-independent actions by chemotherapy.For example, tamoxifen binds to intracellular proteins, includingcalmodulin. Calmodulin may be involved in ER-independentinhibition of breast cancer cell growth by tamoxifen.2.3 A furtherER-independent mechanism has been proposed by Colletta et ai,4who found that tamoxifen enhances the synthesis of an inhibitorygrowth factor in fibroblasts. The possibility that tamoxifen andchemotherapy interact via a mechanism independent of ER issupported by the following analysis of data in the overview:1

Reduction in odds ratio for.ER status Mortality Recurrence

ER poorT only 33(10)% 39 (9)%T plus C 2 (10)% 31 (22)%

ER +

T only 20(12)% 37 (9)%T plus C 5(11)% 38(16)%

ER ++

T only 23(16)% 52 (9)%T plus C 20 (15)% 52 (19)%

Only the tamoxifen-alone effect in the ER-poor group satisfiesthe criterion that a difference of 3 SD or so provides firm evidence ofa treatment effect, with respect to mortality. For recurrence T onlybut not the T plus C consistently meet the criterion. The datatherefore concur with the hypothesis that chemotherapy mayinhibit a mode of action of tamoxifen that is not ER dependent.The ten-year overview analysis now underway may shed further

light on whether this is a purely chance result or reflects theunderlying mode of action of tamoxifen.

Department of Computing,Academic Department of Surgery,

and Department of Biochemical Endocrinology,Royal Marsden Hospital,London SW3 6JJ, UK

R. P. A’HERNM. BAUMM. DOWSETT

1. Early Breast Cancer Trialists’ Collaborative Group. Treatment of early breast cancer:vol I Oxford: Oxford Medical Publications, 1990.

2. Gulino A, Barrera G, Vacca A, et al. Calmodulin antagonism and growth inhibitingactivity of triphenylethylene antiestrogens in MCF-7 human breast cancer cells.Cancer Res 1986; 46: 6274-78.

3. Musgrove EA, Wakeling AE, Sutherland RL. Points of action of estrogen antagonistsand a calmodulin antagonist within the MCF-7 human breast cancer cell cycleCancer Res 1989; 49: 2398-404.

4 Colletta AA, Wakefield LM, Howell FV, et al Anti-oestrogens induce the secretion ofactive transforming growth factor beta from human fetal fibroblasts. Br J Cancer1990; 62: 405-09.

CSF acetyl and butyryl cholinesteraseactivities in children with bacterial

meningitisSIR,-Several workers have reported abnormal levels of

acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inthe cerebrospinal fluid (CSF) of patients with bacterial

meningitis.12 We have measured AChE and BuChE activities inlumbar CSF from 123 control subjects and 75 patients withbacteriologically confirmed meningitis (19 under 1 year; 30 aged1-8, and 26 aged 8-60). 5 ml CSF was centrifuged at 1000 g for 10min and stored at - 7&deg;C for several weeks. AChE activity was

AChE AND BuChE ACTIVITIES IN CSF OF CONTROLS AND OF

PATIENTS WITH BACTERIAL MENINGITIS

Values as mean (SE) in nmol mm-1 ml-1 CSF (no of patients) *p<0 001

measured3 with acetylthiocholine iodide (1 mmol/1) as substratewithout and with 0-05 mmol/1 of a specific BuChE inhibitor(iso-OMPA). BuChE was assayed with butyrylthiocholine iodide1 mmol/1 without and with 01 mmol/l BW284c51 (a specific andreversible inhibitor of AChE).Tune et al’ found that CSF activities of AChE and BuChE

normally increase with age. For AChE, from age 8 to 79, theequation was y=0’127 x +9-10, the average value at age 8 being10-6 nmol min-l m1-1 (U/ml). For BuChE the equation wasy= 0-054 x +5-01. The AChE/BuChE ratio is normally fairlyconstant at 1 8-1 9.5

In patients with bacterial meningitis we found that in infants andin children aged 1-8 AChE and BuChE activities were higher thanthey were in age-matched controls (table). However, in older

patients the mean CSF AChE and BuChE values did not

significantly differ from control values.The source of AChE in CSF may be the small portion of

"naturally soluble" enzyme found in mammalian brain.’’Inflammation would lead to an increase of enzyme secretion’ fromthe intracellular pool of soluble AChE. The origin of CSF BuChE isthought to be plasma8.9 and neuronal and glial cells." IncreasedBuChE activity has been reported in conditions with blood-carrierdamage.2 Thus, the increase in CSF BuChE of infants and childrenwith bacterial meningitis suggests an alteration in the blood/brain,brain/CSF, and/or blood/CSF barriers, leading to an increase in thepassage of serum components. Whether the increase of BuChEarises completely from plasma or partly from brain cells is underinvestigation.

Department of Biochemistyand Molecular Biology,

Faculty of Biology,University of Murcia,30071 Murcia, Spain

P. L. TORNELC. J. VIDAL

1.Dickmann U, Soerensen K, Wiedmann T, Mader M, Felgenhauer K Neuronalacetylcholinesterase in serum and CSF: a prototypic marker for the brain-blood-transfer of proteins? J Clin Chem Clin Biochem 1989; 27: 835

2. Johnson S, Domino EF. Cholinergic activity of cerebro-spinal fluid of patients withvanous neurological diseases. Clin Chim Acta 1971; 35: 421-28.

3. Ellman GL, Courtney DD, Andres V, Featherstone RM. A new and rapidcolorimetric determination of acetylcholinesterase activity Biochem Pharmacol

1961; 1: 88-95.4 Tune L, Gucker S, Folstein M, Oshida L, Coyle TL Cerebrospinal fluid

acetylcholinesterase activity in senile dementia of the Alzheimer type Ann Neurol1985; 17: 46-48.

5. Arendt T, Bigl V, Walther F, Sonntag M. Decreased ratio of CSF acetylcholinesteraseto butyrylcholinesterase activity in Alzheimer’s disease. Lancet 1984; i: 173.

6. Vidal CJ, Chai MSY, Plummer DT The effect of solubilization on the properties andmolecular forms of rat brain acetylcholinesterase Neurochem Int 1981, 3: 229-38.

7. Chubb IW, Hodgson AJ. Release of non-transmitter substances: speciallyacetylcholinesterase Trends Auton Pharmacol 1982; 2: 61-81.

8. Atack J, Perry EK, Bonham JR, Perry RH. Molecular forms of acetylcholinesteraseand butyrylcholinesterase in human plasma and cerebrospinal fluid J Neurochem1987; 48: 1845-50.

9. Rao RV, Gnanamuthu C, Balasubramanian AS. Human cerebrospinal fluid

acetylcholinesterase: evidence for identity between the serum and cerebrospinalfluid butyrylcholinesterase. Clin Chim Acta 1989, 183: 135-146.

10 Koelle GB. The histochemical localisation of cholinesterases in the central nervous

system of the rat. J Comp Neurol 1954; 100: 211-35.

CORRECTION

Severe adverse interaction between pethidine and seleglline -In Thisletter by Dr G. L. Zomberg and colleagues (Jan 26, p 246), the treatmentregimen of the cited case should have read "... ’Sinemet’ 4 tablets (10 mgcarbidopa, 100 mg levodopa per tablet) daily, oral imipramine 175 mg daih.and oral desipramine 25 mg daily."