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ANTIBODY-TARGETED THERAPY OF CANCER
860
ANTIBODY-TARGETED THERAPY OF CANCER
Frequency of tantrums per day during various drug treatments. Imipramine = 150 mg of imipramine per day; Trp 1 and imipramine 1 g tryptophan per day plus imipramine; Trp 1 5-2 ’0 and imipramine 1’ 5 or 2-0 g tryptophan per day plus imipramine; Trp 2-5-3-0 and imipramine = 2 5 or 3 0 g tryptophan per day plus imipramine. Trp 30 and trazodone 3-0 g tryptophan per day plus 200 mg trazodone daily. (During the Trp 25-3-0 and imipramine period there was a ward change which continued for the Trp 3.0 =
=
=
.
and trazodone
treatment
period.)
day, a fourfold reduction from baseline (figure). The level of agitation and pacing decreased. Staff thought that the tantrums and self-assaults were much less intense and much reduced in duration. During this time a self-inflicted massive right pinna haematoma resolved. Subsequently the tryptophan was tapered off, while the trazodone dosage was maintained at 200 mg daily. The blood 5-HT fell to 305 ng/ml at a dose of 2 g tryptophan daily, to 295 ng/ml at 1 g daily, and to 267 ng/ml when the patient was off tryptophan. 6 weeks after the discontinuation of tryptophan, staff felt that the intensity and frequency of self-abuse had worsened and that sleep had deteriorated, so tryptophan was restarted. Temper tantrums remained quiescent during the trazodone treatment. These observations suggest that combination therapy with two relatively safe drugs, tryptophan and trazodone, may hold promise for the treatment of aggressive behaviour. This may be linked to serotonin metabolism and may be linked specifically to patients who manifest abnormal serotonin metabolism. Trazodone appears to be the effective drug for increasing plasma 5-HT levels in this patient. The finding of lowered plasma serotonin levels in a patient with de Lange syndrome raises the possibility that this may be a previously unreported component of this syndrome. We thank Milton Fischer for the 5-HT assays.
Central Wisconsin Center for the Developmentally Disabled
M. O’NEIL N. PAGE W. N. ADKINS
Department of Psychiatry, University of Wisconsin; and Middleton Memorial VA
Hospital,
B. EICHELMAN
M. Depressed 5-hydroxyindole levels associated with hyperactive and aggressive behavior. Arch Gen Psychiatry 1976; 33: 331-36. 2. Yaryura JA, Neziroglu FA Aggressive behavior, clinical interfaces. In: Valzelli L, Morgese L, eds. Aggression and violence: a psychobiological approach. St Vincent: Centro Culturale, 1981: 195-210. 3. Eichelman B, Elliott GR, Barchas JD. Biochemical, pharmacological and genetic aspects of aggression. In: Hamburg D, Trudeau MB, eds. Biobehavioral aspects of aggression. New York: Alan R Liss, 1981: 51-84. 4. Brown GL, Ballenger JC, Minichiello MD, Goodwin FK. Human aggression and its relation to cerebrospinal fluid 5-hydroxyindole acetic acid, 3-methoxy-4hydroxyphenylglycol and homovanillic acid. In: Sandler M, ed. Psychopharmacology of aggression. New York: Raven Press, 1979: 131-48. 5. Yuwiler A, Plotkin S, Geller E, Ritvo E. A rapid accurate procedure for the determination of serotonin in whole blood. Biochem Med 1970; 3: 426-36. 6 Garattini A, de Gaetano G, Samanin R, Bernasconi S, Roncaglioni MC. Effects of trazodone on serotonin in the brain and platelets of the rat. Biochem Pharmacol 1976, 25: 13-16.
Greenberg AS, Coleman
main tumour. Dr Wheldon and Dr O’Donoghue discuss antibody therapy of micrometastases. They state that microscopic disease requires a lower total dose than bulk tumour to achieve sterilisation, allowing a reduction in the administered activity. This is statistically correct for small tumour cell numbers but, since the total mass of tumour is unknown, sufficient activity must be administered to ensure that each metastasis receives a sterilising dose of radiation. We feel that this therapeutic approach should remain experimental until more radioactivity can be deposited into tumour. Diagnostic Research Laboratory, Department of Immunology, Medical School, University of Birmingham, Birmingham B15 2TJ Immuno
Madison, Wisconsin 53705, USA
1.
SIR,-The four replies (Sept 6, pp 579-81) to our June 28 letter in which we suggested that antibody-targeted tumour therapy was unrealistic do not satisfactorily counter our arguments. Our concern was with the systemic therapy of large tumours. Dr Begent and colleagues comment that our calculations fail to take account of the irregular distribution of activity within tumours. They propose that radioactivity is selectively concentrated within well-vascularised tumour sites thereby enhancing the dose to viable tumour. However, viable, inherently radioresistant cells surrounding poorly vascularised tumour must reduce the efficacy of an isotope label emitting short-range beta radiation and drastically reduce the potency of drug or toxin conjugate. Begent et al also refer to preliminary data in animals suggesting that radiolabelled antibody is more effective for tumour killing than external radiation alone.’ This result could be explained by dose fractionation differences. A valid comparison with external beam irradiation would require optimal fractionation of the externally administered dose. The final point they raise concerns second antibody.2 Although this is effective at removing labelled antibody from blood, subsequent deposition of radioactivity into the reticulo endothelial system and bladder would increase normal tissue toxicity. Data have not been published on the distribution of activity within these tissues and the tumour to determine what advantage, if any, is likely to be gained from this technique. Two letters address the question of regional therapy. Dr Epenetos and colleagues agree with our pessimism over successful intravenous therapy but propose that antibodies might still be useful for regional therapy, particularly for intracavity tumours. There are, however, no controlled trials and no comparisons have been made with simpler alternatives such as radioactive colloids. Along similar lines Dr Ward and colleagues have shown that intraperitoneal injection of labelled antibodies leads to high uptake by malignant ascitic cells. They have calculated the dose to these cells by assuming that all the isotope decay energy is absorbed within the cell. This is absurd since the range of both 1251 and 1311 gamma and beta radiation is many times the cell diameter. This means that the dose to single cells is much less than they calculate. In contrast, their calculation of dose to solid tumours is correct and gives results that are similar to those achieved with intravenous therapy and comparable with our data. It is also difficult to see what benefit the patient might gain from therapy targeted towards malignant ascitic cells, which could have little, if any, effect on the
A. VAUGHAN C. CHAPMAN P. W. DYKES P. ANDERSON A. R. BRADWELL
1. Neacy WP, Wessels BW, Bradley E, et al. Comparison of radloimmunotherapy and 4MV external beam therapy of human tumour xenografts in athymic mice. VI World Congress in Immunology (Toronto, 1986), abstr 4.24 11. 2. Begent RJH, Bagshawe KD, Pedley RB, et al. The use of second antibody m radiounmunotherapy. NCI Monogr (in press).
ANTIBODY-GUIDED RADIATION THERAPY VIA THE CSF FOR MALIGNANT MENINGITIS
SIR,-We agree with Dr Vaughan and colleagues (June 28, 492) that the dose of intravenously administered radiolabelled antibody to reach solid tumours is too small to result in therapeutic effects, using current techniques. In cerebral gliomas we found the dose to tumour to be less than 0-005% of the injected dose per g.’ p
ANTIBODY-TARGETED THERAPY OF CANCER
Frequency of tantrums per day during various drug treatments. Imipramine = 150 mg of imipramine per day; Trp 1 and imipramine 1 g tryptophan per day plus imipramine; Trp 1 5-2 ’0 and imipramine 1’ 5 or 2-0 g tryptophan per day plus imipramine; Trp 2-5-3-0 and imipramine = 2 5 or 3 0 g tryptophan per day plus imipramine. Trp 30 and trazodone 3-0 g tryptophan per day plus 200 mg trazodone daily. (During the Trp 25-3-0 and imipramine period there was a ward change which continued for the Trp 3.0 =
=
=
.
and trazodone
treatment
period.)
day, a fourfold reduction from baseline (figure). The level of agitation and pacing decreased. Staff thought that the tantrums and self-assaults were much less intense and much reduced in duration. During this time a self-inflicted massive right pinna haematoma resolved. Subsequently the tryptophan was tapered off, while the trazodone dosage was maintained at 200 mg daily. The blood 5-HT fell to 305 ng/ml at a dose of 2 g tryptophan daily, to 295 ng/ml at 1 g daily, and to 267 ng/ml when the patient was off tryptophan. 6 weeks after the discontinuation of tryptophan, staff felt that the intensity and frequency of self-abuse had worsened and that sleep had deteriorated, so tryptophan was restarted. Temper tantrums remained quiescent during the trazodone treatment. These observations suggest that combination therapy with two relatively safe drugs, tryptophan and trazodone, may hold promise for the treatment of aggressive behaviour. This may be linked to serotonin metabolism and may be linked specifically to patients who manifest abnormal serotonin metabolism. Trazodone appears to be the effective drug for increasing plasma 5-HT levels in this patient. The finding of lowered plasma serotonin levels in a patient with de Lange syndrome raises the possibility that this may be a previously unreported component of this syndrome. We thank Milton Fischer for the 5-HT assays.
Central Wisconsin Center for the Developmentally Disabled
M. O’NEIL N. PAGE W. N. ADKINS
Department of Psychiatry, University of Wisconsin; and Middleton Memorial VA
Hospital,
B. EICHELMAN
M. Depressed 5-hydroxyindole levels associated with hyperactive and aggressive behavior. Arch Gen Psychiatry 1976; 33: 331-36. 2. Yaryura JA, Neziroglu FA Aggressive behavior, clinical interfaces. In: Valzelli L, Morgese L, eds. Aggression and violence: a psychobiological approach. St Vincent: Centro Culturale, 1981: 195-210. 3. Eichelman B, Elliott GR, Barchas JD. Biochemical, pharmacological and genetic aspects of aggression. In: Hamburg D, Trudeau MB, eds. Biobehavioral aspects of aggression. New York: Alan R Liss, 1981: 51-84. 4. Brown GL, Ballenger JC, Minichiello MD, Goodwin FK. Human aggression and its relation to cerebrospinal fluid 5-hydroxyindole acetic acid, 3-methoxy-4hydroxyphenylglycol and homovanillic acid. In: Sandler M, ed. Psychopharmacology of aggression. New York: Raven Press, 1979: 131-48. 5. Yuwiler A, Plotkin S, Geller E, Ritvo E. A rapid accurate procedure for the determination of serotonin in whole blood. Biochem Med 1970; 3: 426-36. 6 Garattini A, de Gaetano G, Samanin R, Bernasconi S, Roncaglioni MC. Effects of trazodone on serotonin in the brain and platelets of the rat. Biochem Pharmacol 1976, 25: 13-16.
Greenberg AS, Coleman
main tumour. Dr Wheldon and Dr O’Donoghue discuss antibody therapy of micrometastases. They state that microscopic disease requires a lower total dose than bulk tumour to achieve sterilisation, allowing a reduction in the administered activity. This is statistically correct for small tumour cell numbers but, since the total mass of tumour is unknown, sufficient activity must be administered to ensure that each metastasis receives a sterilising dose of radiation. We feel that this therapeutic approach should remain experimental until more radioactivity can be deposited into tumour. Diagnostic Research Laboratory, Department of Immunology, Medical School, University of Birmingham, Birmingham B15 2TJ Immuno
Madison, Wisconsin 53705, USA
1.
SIR,-The four replies (Sept 6, pp 579-81) to our June 28 letter in which we suggested that antibody-targeted tumour therapy was unrealistic do not satisfactorily counter our arguments. Our concern was with the systemic therapy of large tumours. Dr Begent and colleagues comment that our calculations fail to take account of the irregular distribution of activity within tumours. They propose that radioactivity is selectively concentrated within well-vascularised tumour sites thereby enhancing the dose to viable tumour. However, viable, inherently radioresistant cells surrounding poorly vascularised tumour must reduce the efficacy of an isotope label emitting short-range beta radiation and drastically reduce the potency of drug or toxin conjugate. Begent et al also refer to preliminary data in animals suggesting that radiolabelled antibody is more effective for tumour killing than external radiation alone.’ This result could be explained by dose fractionation differences. A valid comparison with external beam irradiation would require optimal fractionation of the externally administered dose. The final point they raise concerns second antibody.2 Although this is effective at removing labelled antibody from blood, subsequent deposition of radioactivity into the reticulo endothelial system and bladder would increase normal tissue toxicity. Data have not been published on the distribution of activity within these tissues and the tumour to determine what advantage, if any, is likely to be gained from this technique. Two letters address the question of regional therapy. Dr Epenetos and colleagues agree with our pessimism over successful intravenous therapy but propose that antibodies might still be useful for regional therapy, particularly for intracavity tumours. There are, however, no controlled trials and no comparisons have been made with simpler alternatives such as radioactive colloids. Along similar lines Dr Ward and colleagues have shown that intraperitoneal injection of labelled antibodies leads to high uptake by malignant ascitic cells. They have calculated the dose to these cells by assuming that all the isotope decay energy is absorbed within the cell. This is absurd since the range of both 1251 and 1311 gamma and beta radiation is many times the cell diameter. This means that the dose to single cells is much less than they calculate. In contrast, their calculation of dose to solid tumours is correct and gives results that are similar to those achieved with intravenous therapy and comparable with our data. It is also difficult to see what benefit the patient might gain from therapy targeted towards malignant ascitic cells, which could have little, if any, effect on the
A. VAUGHAN C. CHAPMAN P. W. DYKES P. ANDERSON A. R. BRADWELL
1. Neacy WP, Wessels BW, Bradley E, et al. Comparison of radloimmunotherapy and 4MV external beam therapy of human tumour xenografts in athymic mice. VI World Congress in Immunology (Toronto, 1986), abstr 4.24 11. 2. Begent RJH, Bagshawe KD, Pedley RB, et al. The use of second antibody m radiounmunotherapy. NCI Monogr (in press).
ANTIBODY-GUIDED RADIATION THERAPY VIA THE CSF FOR MALIGNANT MENINGITIS
SIR,-We agree with Dr Vaughan and colleagues (June 28, 492) that the dose of intravenously administered radiolabelled antibody to reach solid tumours is too small to result in therapeutic effects, using current techniques. In cerebral gliomas we found the dose to tumour to be less than 0-005% of the injected dose per g.’ p