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Clinically useful doxorubicin analogues
Cancer Treatment Reviews (1987) 14, 159-161
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Clinically useful doxorubicln an;dogu.~e--~:~e~, ' , ¢
F. A r c a m o n e
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"
,.
,-Q /
Research Laboratories, Farmitalia Carlo Erba, Milan, Italy
As it has been pointed out by Adrien Albert (1) 'the treatment of cancer by drugs is both pharmacodynamic (because both economic and uneconomic cells are part of the same organism) and chemotherapeutic (because it aims to exterminate the uneconomic cells)'. In order to improve the pharmacodynamic properties of the clinically-useful antitumor anthracyclines, the synthesis of new analogues with hopefully lower acute and cumulative side-effects has been carried out in our laboratory since the establishment ofdoxorubicin's efficacy in 1972. Lower acute toxicity relates to the possibility of administering higher dosages with potentially more extensive destruction of cancer cells. Lower cumulative toxicity relates to a higher number of courses of treatment with expected benefit in responsive patients. The rationale taken as the basis of analogue development by structural modification of the anthracycline glycosides was that of avoiding changes in the general molecular architecture and chemical functionalities (in order to keep unaltered the structural requirements for action), whilst modifying those features that might induce variations in the metabolism and pharmacokinetics of the drugs. Development of the chemistry of the anthracycline glycosides (2), both of the sugar and of the aglycone moieties, has allowed a wide spectrum of molecular modifications and synthesis of approximately 400 new glycosides. Among the new derivatives that have reached the clinical stage, one compound, namely epirubicin (4'-epidoxorubicin), is already marketed in different countries in Europe and in Canada. The daunorubicin analogue idarubicin (4'demethoxydaunorubicin) is being tested in Phase II clinical trials and other derivatives under clinical evaluation include 4'-deoxydoxorubicin (esorubicin) and 4'-iodo-4'-deoxydoxorubicin. The clinical activity ofepirubicin against different human cancers is shown in Table 1. The data represent results reported in selected Phase II and III studies published during 1982-1987. The outstanding antitumor efficacy of epirubicin, comparable to that exhibited by doxorubicin, is accompanied by a lower incidence of toxicities, including leukopaenia, anaemia and gastrointestinal disturbances (7). An important property of epirubicin is that, because of the presence of the equatorially-oriented C-4' hydroxyl group, the compound becomes a substrate for a fl-D-glucuronidase. In fact the main metabolite (accounting for more than 30% of the urinary radioactivity after administration of 14Cepirubicin) of epirubicin is the 4'-O-fl-D-glucuronide, a derivative devoid of biological activity (4). The detoxification consequent to the conjugation is considered to account for the lower incidence of toxic side effects in patients receiving epirubicin as compared with those taking doxorubicin. One important aspect of the improved therapy with epirubicin is that the total number of cases ofcardiotoxicity was only 40, of which 25% proved fatal, 0305-7372/87/3&40159 + 03 $03.00/0
© 1987 Academic Press Limited 159
F. ARCAMONE
160
Table 1. Clinical activity of epirubicin against different solid tumors
Disease Advanced breast cancer Advanced ovarian cancer Gastric cancer Pancreatic cancer Hepatocellular carcinoma Colorectal cancer Soft-tissue sarcomas Head and neck NH-Lymphornas
Total evaluable cases
Completeand partial remissions
Response rate
442* 274* 144* 73* 83 190 86 65* 137"
204 172 40 17 14 5 15 20 112
46 63 28 23 17 3 17 31 82
* Single agent + combinations.
in a population of 4955 unselected patients, rece!ving dosages in the range of 1 1-1700 m g / m 2, with the percentage incidence becoming greater than 1% only at cumulative dosages surpassing 900 m g / m 2. A recent example of better tolerability is represented by the Italian study comparing FEC versus FAC (both containing 50 mg anthracycline) in 500 patients, showing distinctly lower toxicity in the patients treated with FEC, although the survival curves of the two arms are practically superimposable. Idarubicin was selected for clinical trial on the basis of the high potency and oral activity in experimental murine tumours, especially in transplantable leukaemias, coupled with distinctly lower cardiotoxicity at equimyelotoxic doses when compared with doxorubicin. This derivative, similar to the parent c o m p o u n d daunorubicin, is extensively converted both in laboratory animals and in h u m a n patients into the 13-dihydro derivative idarubicinol (6). This compound, characterized by a slow elimination rate, is apparently responsible for the advantageous pharmacological properties ofidarubicin. As concluded at a recent meeting (International Symposium on T h e r a p y of Acute Leukemias, Rome, February 1987) (a) idarubicin is active in relapsed and refractory A N L L patients, (b) no cardiotoxicity was observed even in patients pretreated with anthracyclines, (c) idarubicin induces p r o m p t remission in adult and elderly patients with A N L L (a possible advantage for bone marrow transplantation) and (d) it is active when administered orally. Oral administration has also given therapeutically useful results in some solid tumors, especially in breast cancer (5). Esorubicin and 4'-iodo-4'-deoxydoxorubicin are two new doxorubicin analogues lacking the hydroxyl group at C-4'. The former has entered broad phase I I clinical trials in Europe and in the U.S.A. The second derivative is characterized by a lower p K value and consequently high lipophilicity at neutral pH. Preclinical tests have shown 4'-iodo-4'deoxydoxorubicin to be active in doxorubicin-resistant murine experimental leukaemias, to be more effective than the parent c o m p o u n d in the Lewis lung carcinoma of the mouse, and to be active when given orally (3).
References
1. Albert, A. (1984) Selective Toxicity seventh edition. London: Chapman & Hall. 2. Arcamone, F. (1981) Doxorubicin, Anticancer Antibiotics. New York: Academic Press.
CLINICALLY USEFUL DOXORUBICIN ANALOGUES
161
3. Barbieri, B., Giuliani, F. C., Bordoni, T., Casazza, A. M., Geroni, C., Bellini, O., Suarato, A., Gioia, B., Penco, S. & Arcamone, F. (1987) Chemical and biological characterization of 4'-Todo-4'-deoxydoxo-rubicin. Cancer Res. 47" 4001. 4. Cassinelli, G., Configliacchi, E., Penco, S., Rivola, G., Arcamone, F., Pacciarini, A. & Ferrari, L. (1984) Separation, characterization, and analysis ofepirubicin (4'-epidoxo-rubicin) and its metabolites from human urine. Drug Metab. Di~p. 12" 506. 5. Ganzina, F., Pacciarini, M. A. & Di Pietro, N. (1986) Invest. New Drugs 4: 85. 6. Penco, S., Cassinelli, G., Vigevani, A., Zini, P., Rivola, G. & Arcamone, F. (1985) Daunorubicin aldo-keto reductases: enantioface differential reduction of the side-chain carbonyl group of anti-tumor anthracyclines. Gazz. Chim. ltal. 115: 195. 7. Tanaassia, V., Armand, J. B., Kolarich, K., Szanto, J., Lorusso, V., Seeber, S. and Tattersall, M. H. N. (1986) Abstracts qJ" Symposium on Farmorubicin ( Epirubicin ) , Fourteenth International Cancer Congress, Budapest, Hungary, 21 27 August, Karger: Basel.
,, "--.
"4
Clinically useful doxorubicln an;dogu.~e--~:~e~, ' , ¢
F. A r c a m o n e
....."'~"'~....
"
,.
,-Q /
Research Laboratories, Farmitalia Carlo Erba, Milan, Italy
As it has been pointed out by Adrien Albert (1) 'the treatment of cancer by drugs is both pharmacodynamic (because both economic and uneconomic cells are part of the same organism) and chemotherapeutic (because it aims to exterminate the uneconomic cells)'. In order to improve the pharmacodynamic properties of the clinically-useful antitumor anthracyclines, the synthesis of new analogues with hopefully lower acute and cumulative side-effects has been carried out in our laboratory since the establishment ofdoxorubicin's efficacy in 1972. Lower acute toxicity relates to the possibility of administering higher dosages with potentially more extensive destruction of cancer cells. Lower cumulative toxicity relates to a higher number of courses of treatment with expected benefit in responsive patients. The rationale taken as the basis of analogue development by structural modification of the anthracycline glycosides was that of avoiding changes in the general molecular architecture and chemical functionalities (in order to keep unaltered the structural requirements for action), whilst modifying those features that might induce variations in the metabolism and pharmacokinetics of the drugs. Development of the chemistry of the anthracycline glycosides (2), both of the sugar and of the aglycone moieties, has allowed a wide spectrum of molecular modifications and synthesis of approximately 400 new glycosides. Among the new derivatives that have reached the clinical stage, one compound, namely epirubicin (4'-epidoxorubicin), is already marketed in different countries in Europe and in Canada. The daunorubicin analogue idarubicin (4'demethoxydaunorubicin) is being tested in Phase II clinical trials and other derivatives under clinical evaluation include 4'-deoxydoxorubicin (esorubicin) and 4'-iodo-4'-deoxydoxorubicin. The clinical activity ofepirubicin against different human cancers is shown in Table 1. The data represent results reported in selected Phase II and III studies published during 1982-1987. The outstanding antitumor efficacy of epirubicin, comparable to that exhibited by doxorubicin, is accompanied by a lower incidence of toxicities, including leukopaenia, anaemia and gastrointestinal disturbances (7). An important property of epirubicin is that, because of the presence of the equatorially-oriented C-4' hydroxyl group, the compound becomes a substrate for a fl-D-glucuronidase. In fact the main metabolite (accounting for more than 30% of the urinary radioactivity after administration of 14Cepirubicin) of epirubicin is the 4'-O-fl-D-glucuronide, a derivative devoid of biological activity (4). The detoxification consequent to the conjugation is considered to account for the lower incidence of toxic side effects in patients receiving epirubicin as compared with those taking doxorubicin. One important aspect of the improved therapy with epirubicin is that the total number of cases ofcardiotoxicity was only 40, of which 25% proved fatal, 0305-7372/87/3&40159 + 03 $03.00/0
© 1987 Academic Press Limited 159
F. ARCAMONE
160
Table 1. Clinical activity of epirubicin against different solid tumors
Disease Advanced breast cancer Advanced ovarian cancer Gastric cancer Pancreatic cancer Hepatocellular carcinoma Colorectal cancer Soft-tissue sarcomas Head and neck NH-Lymphornas
Total evaluable cases
Completeand partial remissions
Response rate
442* 274* 144* 73* 83 190 86 65* 137"
204 172 40 17 14 5 15 20 112
46 63 28 23 17 3 17 31 82
* Single agent + combinations.
in a population of 4955 unselected patients, rece!ving dosages in the range of 1 1-1700 m g / m 2, with the percentage incidence becoming greater than 1% only at cumulative dosages surpassing 900 m g / m 2. A recent example of better tolerability is represented by the Italian study comparing FEC versus FAC (both containing 50 mg anthracycline) in 500 patients, showing distinctly lower toxicity in the patients treated with FEC, although the survival curves of the two arms are practically superimposable. Idarubicin was selected for clinical trial on the basis of the high potency and oral activity in experimental murine tumours, especially in transplantable leukaemias, coupled with distinctly lower cardiotoxicity at equimyelotoxic doses when compared with doxorubicin. This derivative, similar to the parent c o m p o u n d daunorubicin, is extensively converted both in laboratory animals and in h u m a n patients into the 13-dihydro derivative idarubicinol (6). This compound, characterized by a slow elimination rate, is apparently responsible for the advantageous pharmacological properties ofidarubicin. As concluded at a recent meeting (International Symposium on T h e r a p y of Acute Leukemias, Rome, February 1987) (a) idarubicin is active in relapsed and refractory A N L L patients, (b) no cardiotoxicity was observed even in patients pretreated with anthracyclines, (c) idarubicin induces p r o m p t remission in adult and elderly patients with A N L L (a possible advantage for bone marrow transplantation) and (d) it is active when administered orally. Oral administration has also given therapeutically useful results in some solid tumors, especially in breast cancer (5). Esorubicin and 4'-iodo-4'-deoxydoxorubicin are two new doxorubicin analogues lacking the hydroxyl group at C-4'. The former has entered broad phase I I clinical trials in Europe and in the U.S.A. The second derivative is characterized by a lower p K value and consequently high lipophilicity at neutral pH. Preclinical tests have shown 4'-iodo-4'deoxydoxorubicin to be active in doxorubicin-resistant murine experimental leukaemias, to be more effective than the parent c o m p o u n d in the Lewis lung carcinoma of the mouse, and to be active when given orally (3).
References
1. Albert, A. (1984) Selective Toxicity seventh edition. London: Chapman & Hall. 2. Arcamone, F. (1981) Doxorubicin, Anticancer Antibiotics. New York: Academic Press.
CLINICALLY USEFUL DOXORUBICIN ANALOGUES
161
3. Barbieri, B., Giuliani, F. C., Bordoni, T., Casazza, A. M., Geroni, C., Bellini, O., Suarato, A., Gioia, B., Penco, S. & Arcamone, F. (1987) Chemical and biological characterization of 4'-Todo-4'-deoxydoxo-rubicin. Cancer Res. 47" 4001. 4. Cassinelli, G., Configliacchi, E., Penco, S., Rivola, G., Arcamone, F., Pacciarini, A. & Ferrari, L. (1984) Separation, characterization, and analysis ofepirubicin (4'-epidoxo-rubicin) and its metabolites from human urine. Drug Metab. Di~p. 12" 506. 5. Ganzina, F., Pacciarini, M. A. & Di Pietro, N. (1986) Invest. New Drugs 4: 85. 6. Penco, S., Cassinelli, G., Vigevani, A., Zini, P., Rivola, G. & Arcamone, F. (1985) Daunorubicin aldo-keto reductases: enantioface differential reduction of the side-chain carbonyl group of anti-tumor anthracyclines. Gazz. Chim. ltal. 115: 195. 7. Tanaassia, V., Armand, J. B., Kolarich, K., Szanto, J., Lorusso, V., Seeber, S. and Tattersall, M. H. N. (1986) Abstracts qJ" Symposium on Farmorubicin ( Epirubicin ) , Fourteenth International Cancer Congress, Budapest, Hungary, 21 27 August, Karger: Basel.