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ICRF-187 AND RAZOXANE IN CANCER TREATMENT
721
that the beneficial effect of fish-oil also lasted longer than the four-week washout period at the crossover time. Thus benefit carried over into the placebo phase and would have had the effect of minimising the advantage of active treatment.
The response to this form of dietary and pharmacological of marine fish-oils is more dramatic in biochemical than therapeutic terms; most rheumatologists would expect to achieve better relief of symptoms with non-steroidal antiinflammatory drugs. Nevertheless, provided the therapy was harmless, there might be some merit in recommending dietary modification which involved increased fish consumption with reduction in red meat, particularly to those patients who need to feel that they are doing something to help themselves. However, marine fish oils have effects on other important metabolic pathways. For example, EPA can substitute for AA in platelets, thereby reducing the amount of thromboxane Az and increasing thromboxane A3, which results in decreased platelet aggregation.8 Dietary manipulation of essential fatty acids alters the immune response in laboratory animals.9 Evidence from animal models of experimental arthritis also shows that the disease worsens in those treated with EPA.1O Thus, dietary modification is not invariably good, and there is concern about vitamin A toxicity and increased cholesterol levels in American patients who purchase over-the-counter cod-liver oil preparations as a cheap alternative to prescription use
products. Two major goals
in effective treatment of rheumatoid slow the radiological and functional progression of the disease. So far there is no evidence that marine fish-oils are useful in this respect. However, such studies would need to be long-term and use very sensitive systems of assessment. Whilst fish-oils have been shown to have minor anti-inflammatory properties, if the same criteria for demonstrating efficacy and tolerability were applied to this form of therapy as to new anti-arthritic drugs, it is unlikely that a product licence would be granted. arthritis
are
to
ICRF-187 AND RAZOXANE IN CANCER TREATMENT ALL too often the unpredictability of drug development results in deep depression and frustration, but just occasionally exciting and potentially valuable results emerge unexpectedly. Razoxane (ICRF-159) and its D-isomer
(ICRF-187), originally developed as anticancer drugs, received extensive testing both in the laboratory, where they were active, and in the clinic, where they were not. Nevertheless, interest in these substances has been maintained principally because of subtle, previously unknown, and unsuspected activities that they were found to have experimentally and that could have an impact, albeit indirectly, on cancer treatment. Perhaps the two most interesting of these activities are prevention of metastasis and prevention of doxorubicin-induced cardiotoxicity.
At the last meeting of the American Society of Clinical Oncology in Atlanta in May, Dr Mark Green and colleagues of the New York University Medical Center gave details of 82 patients in a trial comparing the effects of 5-fluorouracil, doxorubicin (’Adriamycin’), and cyclophosphamide (FAC) with and without ICRF-187 on heart failure, left ventricular ejection fraction, and histological changes in endomyocardial biopsies. All the patients had metastatic breast cancer and were carefully matched, particularly for cardiac risk factors. Treatment was not stopped at the usual doselimiting toxicity for doxorubicin of 550 mg/m2 but continued until a cardiac end-point was attained. Tumour responses and myelosuppression were unaffected by
administration of ICRF-187. Clinical evidence of cardiotoxicity developed in 6 of 41 patients receiving ICRF-187 and in three times as many (19/41) controls. Histological changes in the myocardium were apparent in 5 of 11 patients treated with FAC alone but in none of the 9 patients in the ’FAC plus ICRF-187 group. An identical study is underway in the Netherlands and the outcome is awaited. It will also be of considerable interest to see how far the dose-limiting cardiotoxic dose can be extended and whether, at this higher dose, response rate and duration of response will be significantly improved. Many substances have already been examined for their ability to prevent the cardiotoxicity of doxorubicin and some have been claimed to be effective, but none have stood the test of clinical trials. The fundamental animal work showing that razoxane and later ICRF-187 prevented doxorubicin cardiotoxicity began fifteen years ago and has been pursued most keenly at the Food and Drug Administration laboratories in Washington, DC, by Dr E. Herman and co-workers and it is to him that the credit for this important
discovery belongs. Equally empiric and no less important is the finding that when razoxane is given as adjuvant treatment in patients with Dukes’ group C colorectal cancer, it does not cause regressions of tumours, but it reduces the incidence and delays the appearance of liver metastases.1 Thus it most probably contributes directly to the significant reduction in recurrence and increase in survival of these patients. These two actions of razoxane and ICRF-187 indicate that drugs with indirect anticancer activity could profoundly affect cancer treatment in the near future.
MYELOPATHY HAND THERE are probably more eponymous neurological signs associated with the hand and arm than with any other part of the body. This is not simply because the upper limb is easily accessible to examination, but more a reflection of the vast quantity of neurons at cortical level devoted to hand and finger movement. Bedside. ability to detect early involvement of the pyramidal tract is an enviable skill; whilst minor dysfunction in this pathway readily provokes symptoms, physical signs may be elusive to begin with. Muscle tone is traditionally assessed first; probably the most sensitive method is to measure the degree of opposition to
8. Fischer
S, Weber PC. TXA3 is formed in human platelets after dietary EPA. Biochem Biophys Res Comm 1983; 116: 1091-99. 9. Good RA, West A, Fernandes G. Nutritional modulation of immune responses. Fed Proc 1980; 39: 3048-104. in rats
immunized with type II
MD, Speyer JL, Stecy P, et al. ICRF-187 (ICRF) prevents doxorubicin (DOX) cardiotoxicity (CTOX): results of a randomized clinical trial. Proc ASCO 1987, 6: 28.
10. Prickett JD, Trentham DE, Robinson DR.Dietary fish-oil augments the induction of
arthritis
1. Green
collagen. J
Immunol 1984; 132: 725-29.
2. Hellmann K, Gilbert J, Evans M, Cassell P, Taylor R. Effect of razoxane on metastases
from colorectal
cancer. Clin
Exp Metastasis 1987; 5: 3-8.
that the beneficial effect of fish-oil also lasted longer than the four-week washout period at the crossover time. Thus benefit carried over into the placebo phase and would have had the effect of minimising the advantage of active treatment.
The response to this form of dietary and pharmacological of marine fish-oils is more dramatic in biochemical than therapeutic terms; most rheumatologists would expect to achieve better relief of symptoms with non-steroidal antiinflammatory drugs. Nevertheless, provided the therapy was harmless, there might be some merit in recommending dietary modification which involved increased fish consumption with reduction in red meat, particularly to those patients who need to feel that they are doing something to help themselves. However, marine fish oils have effects on other important metabolic pathways. For example, EPA can substitute for AA in platelets, thereby reducing the amount of thromboxane Az and increasing thromboxane A3, which results in decreased platelet aggregation.8 Dietary manipulation of essential fatty acids alters the immune response in laboratory animals.9 Evidence from animal models of experimental arthritis also shows that the disease worsens in those treated with EPA.1O Thus, dietary modification is not invariably good, and there is concern about vitamin A toxicity and increased cholesterol levels in American patients who purchase over-the-counter cod-liver oil preparations as a cheap alternative to prescription use
products. Two major goals
in effective treatment of rheumatoid slow the radiological and functional progression of the disease. So far there is no evidence that marine fish-oils are useful in this respect. However, such studies would need to be long-term and use very sensitive systems of assessment. Whilst fish-oils have been shown to have minor anti-inflammatory properties, if the same criteria for demonstrating efficacy and tolerability were applied to this form of therapy as to new anti-arthritic drugs, it is unlikely that a product licence would be granted. arthritis
are
to
ICRF-187 AND RAZOXANE IN CANCER TREATMENT ALL too often the unpredictability of drug development results in deep depression and frustration, but just occasionally exciting and potentially valuable results emerge unexpectedly. Razoxane (ICRF-159) and its D-isomer
(ICRF-187), originally developed as anticancer drugs, received extensive testing both in the laboratory, where they were active, and in the clinic, where they were not. Nevertheless, interest in these substances has been maintained principally because of subtle, previously unknown, and unsuspected activities that they were found to have experimentally and that could have an impact, albeit indirectly, on cancer treatment. Perhaps the two most interesting of these activities are prevention of metastasis and prevention of doxorubicin-induced cardiotoxicity.
At the last meeting of the American Society of Clinical Oncology in Atlanta in May, Dr Mark Green and colleagues of the New York University Medical Center gave details of 82 patients in a trial comparing the effects of 5-fluorouracil, doxorubicin (’Adriamycin’), and cyclophosphamide (FAC) with and without ICRF-187 on heart failure, left ventricular ejection fraction, and histological changes in endomyocardial biopsies. All the patients had metastatic breast cancer and were carefully matched, particularly for cardiac risk factors. Treatment was not stopped at the usual doselimiting toxicity for doxorubicin of 550 mg/m2 but continued until a cardiac end-point was attained. Tumour responses and myelosuppression were unaffected by
administration of ICRF-187. Clinical evidence of cardiotoxicity developed in 6 of 41 patients receiving ICRF-187 and in three times as many (19/41) controls. Histological changes in the myocardium were apparent in 5 of 11 patients treated with FAC alone but in none of the 9 patients in the ’FAC plus ICRF-187 group. An identical study is underway in the Netherlands and the outcome is awaited. It will also be of considerable interest to see how far the dose-limiting cardiotoxic dose can be extended and whether, at this higher dose, response rate and duration of response will be significantly improved. Many substances have already been examined for their ability to prevent the cardiotoxicity of doxorubicin and some have been claimed to be effective, but none have stood the test of clinical trials. The fundamental animal work showing that razoxane and later ICRF-187 prevented doxorubicin cardiotoxicity began fifteen years ago and has been pursued most keenly at the Food and Drug Administration laboratories in Washington, DC, by Dr E. Herman and co-workers and it is to him that the credit for this important
discovery belongs. Equally empiric and no less important is the finding that when razoxane is given as adjuvant treatment in patients with Dukes’ group C colorectal cancer, it does not cause regressions of tumours, but it reduces the incidence and delays the appearance of liver metastases.1 Thus it most probably contributes directly to the significant reduction in recurrence and increase in survival of these patients. These two actions of razoxane and ICRF-187 indicate that drugs with indirect anticancer activity could profoundly affect cancer treatment in the near future.
MYELOPATHY HAND THERE are probably more eponymous neurological signs associated with the hand and arm than with any other part of the body. This is not simply because the upper limb is easily accessible to examination, but more a reflection of the vast quantity of neurons at cortical level devoted to hand and finger movement. Bedside. ability to detect early involvement of the pyramidal tract is an enviable skill; whilst minor dysfunction in this pathway readily provokes symptoms, physical signs may be elusive to begin with. Muscle tone is traditionally assessed first; probably the most sensitive method is to measure the degree of opposition to
8. Fischer
S, Weber PC. TXA3 is formed in human platelets after dietary EPA. Biochem Biophys Res Comm 1983; 116: 1091-99. 9. Good RA, West A, Fernandes G. Nutritional modulation of immune responses. Fed Proc 1980; 39: 3048-104. in rats
immunized with type II
MD, Speyer JL, Stecy P, et al. ICRF-187 (ICRF) prevents doxorubicin (DOX) cardiotoxicity (CTOX): results of a randomized clinical trial. Proc ASCO 1987, 6: 28.
10. Prickett JD, Trentham DE, Robinson DR.Dietary fish-oil augments the induction of
arthritis
1. Green
collagen. J
Immunol 1984; 132: 725-29.
2. Hellmann K, Gilbert J, Evans M, Cassell P, Taylor R. Effect of razoxane on metastases
from colorectal
cancer. Clin
Exp Metastasis 1987; 5: 3-8.