Cancer Treatment Reviews (1978) 5, 199-207 Maytanslne Brian F. Issell* and Stanley T. Crooite Department of Clinical Cancer Research, Bristol Laboratories, Syracuse, New York 13201, U,S,A. Introduc~on Maytansine is a naturally occurring ansa macrolide with antitumor activity. It possesses metaphase arrest antimitotic properties which are also properties of the vinca alkaloids vincristine and vinb~astine. Yreclinical rodent tumor testing demonstrated high activity at very low dose levels and antitumor activity over a wide dose range. Phase I clinical testing by the National Cancer Institute (NCI) has now largely been completed and the compound isin Phase II trials. The purpose of this paper is to review the available information on maytansine, especially with respect to an evaluation of its potential clinical usefulness. History Maytansine was first isolated by Kupchan and coworkers (I 1, 12) in 1971 from alcoholic extracts of the East African shrub Maytenus serrata (formerly known as M. ovatus) and later from the wood and bark ofMaytenus buchananii, It was the first ansa macrolidc to be isolated from a plant rather than a micro-organism. Previously described ansa macrolides had demonstrated inhibition of bacterial DNA-dependent RNA polymerase (8, 17) and -¢iral RNA-directed DNA polymerase (22), but maytansine was the first compound of this class to show significant antitumor activity (11, 12). It was found to be highly actlve against the mouse P388 lymphocytic leukemia and to also show activity against the L 1210 mouse leukemia, the Lewis lung carcinoma and I3-16 melanoma solid tumors (11, 12). Encouraged by its preclinical activity the NCI initiated Phase I clinical testing in 1976. * Address reprint requests to: Brian F. Isaell, R{. D., Bristol Laboratories, P.O. Box 657, Syracuse, New York 1320I; U.S.A. 199 0305-7372]781040 199 + 09~g)2.00/0 (~ 1978 Academic Press Inc. (London) Ltd.
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`The ansa macrolide class of compounds of which maytansine is a member includes the
`Saxnycins and streptovarcins. The shctural formula of maytansine is shown in Figure
`1, and consists of an aromatic nucleus to which a macrocyclic aliphatic bridge is attached
`at two non-adjacent positions. Two homologue compoun&s are genefaily isolated with
`maytarnine. These are maytanprine and maytanbutine and differ from m a y m i n e by a
`methyl group in the h t
` case and two methyl groups in the sec~nd case as shown in
`Figure 1. Both homolopes have antitumor activity although t~ a l&er extent than
`maytansine in the P388 system (14). Naytansine can be differentiated from its homolo-
`gues by chromatography in an ethyl acetate system on silica gel, using ultraviolet light
`$0 visualize the zona (9).
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`Flgum Z. Stntawd formufa of magrtarasinc and Romologues.
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`The structure activity relationships in the rnaytamh~id ansa macrolids have recently
`been reported for a small number of compounds (1 4). The carbinol amide and ester chain
`off 6-3 appear to be necessary for significant antitumor activity (12, 14.).
`The extraction of maytansine fiom plant sources has resulted in low yields of active com-
`pound. A search for a rnicrobi01ogical source has recently been reported to be successfd
`(10) and tfhiS new source will hopefully ref eve the suppIy problem which have hindered
`the deveIopment of maytansine to date.
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`Maytansine, like the vinca alkaloids vincdstine and vinblastine, is a mitotic inhibitor.
`Treatment of L 12 10 cells in yitro with maytansine resulted in 67% of the cells accumulated
`in mitosis whereas the untreated control celb demonstrated a mitotic index ranging
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`I~IAYTANSINE CANCER THERAPY 20I between 3.2 and 5.8% (21). Flo w microfluorimetry analysis of LI210 cells during ex- posure to maytansine indicated a shift in the distribution of DNA to a single peak, rep- resenting the DNA of cells in G2 & M Phases (23). Experiments with sea urchin eggs and clam eggs suggested that maytansine inhibited mitosis by interfering with the formation of microtubules by inhibiting the polymerization of the microtuble protein, tubulin (19). The effects ofmaytansine at 10 -7 M concentration on DNA, RNA and protein syntheses were e=~amined in routine leukemia cell cultures (21, 22). DNA synthesis was inhibited to the greatest extent. In the P388 cells DNA synthesis was 14% ofcontrols whereas RNA and protein syntheses were 46 and 485/o of controls respectively. Unlike other ansa mac- rolides, maytansine did not inhibit Escheriehia coli I~.tNA polymerase activity at con- centrations as high as 10-" M (22). As an antimitotic agent maytansine was found to be approximately 100 times more potent than vincristine in sea urchin eggs and 20 times more potent in Chinese Hamster ovary-K cells in tissue culture (20). However both drugs inhibited in vitro polymerization of tubulin at about the same concentrations (19). The differences in cellular activity between the two drugs may be explained by differences in uptake. In experiments with rat brain tubulin, maytansine and vincristine were found to bind reversibly and com- petitively (15). ~ Both drugs were found to share a common binding site although an ad- ditional site Specific for maytansine seemed to be present (15): The effects of maytansine and vincristine on the flow microfluorimetric characteristics of P388 murine leukemia in vivo have been compared. Similar cytokinetic effects were seen" after the administration of both drugs although the effects were greater and more persistent with maytansine. Morphologically both drugs produced some degree of multinucleation and endoredupli- cation and vincristine also produced a population of cells with a DNA content, by fluorescence, eqtfivalent to octaploidy. Pre¢l;nical acdvi~ In vitro P388, L1210 and LY5178 murine leukemic cell suspensions were found to be inhibited "by maytansine at doses of 10 -3 to 10 -7 ttg/ml, with the P388 linebeing the most sensitive (21). Maytansine was shown tO be an active inhibitor of in vitro growth of human nasopharyngeal carcinoma cells and the human lymphoblast leukemia line C.E.M. was inhibited by doses as 10w as 10-3 ~tg/ml (21). Maytansine has also been shown to be activein uivo (21). The P388 lymphocytic leukemia system was inhibited over a 50- to 100-fold dosage range which suggested a high therapeutic index.(l !)- Also maytansine was shown to have significant inhibitory activity against the L 1210 mouse leukem!a, the Lewis lung carcinoma and B- 16 melano- carcinoma solid murine tumor systems_(/1). The optimal antitumor dose was 25 btg/kg/day for I0 consecutive days intraperitoneally for the P388, L1210 and B-16 tumor systems (21) and 32. ~tg/kg/day for 9 consecutive days for the Lewis lung carcinoma (9). Maytansine treatment of mice inoculated with P388 cells in~acerebrally resulted in only minimal antitumor activity and suggested that the drug does easily penetrate the blood-brain barrier in the mouse (21)o In the P388 in Oivo system maytansine was most active when given by a 3-hourly dosage schedule on Days 1, 5 and 9 (9). Maytansine was compared with vincristine in oivo and in vincristine-sensitive and resistant cell lines (22). Cross resistance was observed but maytansine was active against sensitive strains at a tenfold lower concentration than vincristine.
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`202 B. F. ISSELL AND S. T. CROOKE Precllnlca~ toxicity Acute toxicitF In the mouse the lethal dose in 10% of the animals treated (LDIo) was 1.22 mg/m 2 for males and 1.29 mg/m 2 for females when maytansine was given by intraperitoneal injection. Histopathologic evaluation ofselected organs from the mice revealed lymphoid depletion ofsplenic follicles, fatty change and mild granular degeneration of hepatoevtes. No other drug related changes were observed (9). In the rat after a single subcutaneous injection the LDa0 was of the same magnitude as for the mouse at 1.22 mg/m 2 (0.4 mg/kg). Histologically, neerotizing lesionswereseenin the gastrointestinal tract mucosa, thymus, spleen, bone marrow and testes. Of considerable interest is the reported observation of hemorrhagic lesions of the brain, m0nonuclear infiltration in the meninges and chromatolysis and vacuolation of dorsal root ganglion cells (18). In the beagle dog (9) the toxic dose low was 0.3 mg/m 2 when maytansine was given as a single intravenous dose and 0.75 mg/m 2 when divided over 5 daily administrations. In the Rhesus monkey the toxic dose low was 0.45 mg/m 2 when divided over 5 daily intra- venous injections (9). Chronic toxicity Multiple dose and more chronic treatment schedules in the beagle dog and monkey (9), resulted in pancreatic acinar cell degeneration and nephrosis; Increased mitotic activity was observed in numerous tissues including the pancreas, esophagus, stomach, small and large intestines, adrenal cortex, renal pelvis ureter, urinary bladder, and skin. The results from these studies suggested that toxicity from maytansine was dose related, reversible (except for histopathologictiver lesions) and non cumulative. Neurotoxicity The neurotoxic effects of maytansine, vincristine and vinblastine were compared in mice by observing hind limb paralysis following administration of toxic doses (21). Vincristine was found to be neurotoxic causing 80 to 90~/o ofrnice to develop hind limb paralysis. In contrast vinblastine was not neurotoxic at the doses given and maytansine produced only mild hind limb paralysis in 10% of the mice receiving daily subcutaneous doses of 1.20 mg/m 2. Teratogenicity Pregnant mice were treated with single injections of maytansine on Days 6, 7 and 8 of gestation and their fetuses examined for malformation of Day 17 of gestation (21). Both embryotoxic and teratogenic effects which appeared to be dose related were demon- strated. They were most marked when maytansine was administered on Day 7 of gestation. Injection site When maytansine was given by subcutaneous injection in several animals a local tissue reaction with inflammation and fibrosis was observed (9).
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`~L~YTANSINE CANCER THERAPY 203 l~harxnacolt4netlcs No satisfactory methodology has thus thr been developed for detecting the low concentra- tions of maytansine present in human blood and tissues following dosage in the clinical range. A quantitative microbiological assay using Penidtlium avetlaneum OC-4376 has been described but the sensitivity of this assay is inadequate (7). The competitive dis- placement ofaH-vincristine by maytansine on rat brain tubulin (16), has been investigated as a quantitative assay of maytansine, but has yet to be proven effective. Chabner et al. (5) using this methodology found that the assay was insufficiently sensitive to measure the low serum levels of maytansine present at clinically tolerated doses. The development of g radioimmunoassay has been hindered to date by an insufficient supply of maytansine to induce animal antibody production. The future supply of maytansine by a fermentation process (10) rather than by extraction of plants will hope- fully allow quantities sufficient for radioimmunoassay development. Clinical experience Maximum tolerated dose The maximum tolerated doses (MTD) generated from the National Cancer Institute Phase I and early Phase II trials are shown in Table 1. There was a good agreement among the dose levels reported from the contributing institutions. The MTD was in the 2 mg/m 2 range when maytansine was given every 3 to 4 weeks either as a single dose or divided over 3 daily doses. When given by weekly injections in the M.D. Anderson Phase II study (3) doses between 0.75 and 1.25 mg/m z were the maximum tolerated. Toxieities Gastrointestinal. The most common and dose limiting toxicities were gastrointestinal and consisted primarily of nausea, vomiting and diarrhea, often followed by constipation. These toxicities appeared to be dose related. Table I. Maximum tolerated doses of rnay~_~sine according to schedule Institution Maximum tolerated Interval between Dose limiting (Reference) dose (mg/m 2) Schedule course (days) toxicity Mayo Clinic (6) 2.25 Divided dose 28 Gastrointestinal Da~ 1. 3, 5 Weakness National Cancer 2.0 Single dose 21 Gastrointestinal Inztitute (5) Day 1 M.D. Anderson HospitaI Phase I (4) 1.8-2.1 Divided dose 21 Gasgroin~est inal Day 1-3 Phase II (3) 1.8 Divided dose 14 Gastrointestinal Day 1-3 Phase II (3) 0.75-1.25 Divided dose 7 Gastrointestinal Day 1-3 Sidney Farber (2) 2.0-2.5 Divided dose 21 Gastrointestinal Day I-5
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`204 B. F. ISSELL AND S. T. CROOKE In the M. D, Anderson experience reported by Cabanillas et aL (, toxicities were first seen at a dose of 1.2 mg/m 2 (0.4 tng/m2/day × 3 days) and consisted of nausea and vomiting which became progressively more severe at higher dose levels and lead to severe dehydration within a few hours. Eagan et al. (6) from the Mayo Cllinie reported that severe nausea and vomiting were usually observed in patients receiving doses of 1.8 mg/m a or greater. These toxicities generally began on or about Day 4 or 5 and persisted for I to 5 days. They were sometimes accompanied by abdominal cramps and wateryfdiarrhea; Chabner et at..(5) at the NCII reported that 2 of 3 patients treated at a dose of 2 mg/m 2 developed ~ severe diarrhea lasting 5 to14 daysi In the Sidney Farber experience reported by Blum etai. (2) nausea and diarrhea started around Day 3 and ended by Day 8. Patients also reported consti- pation during the second week of therapy. Othergastrointestinal related syrnptoms were anorexia and taste change lasting until the second week of therapy. Central nervous system. Other incapacitating toxicities were considered to be due to the effect of maytansine on the central nervous system. These consisted of profound weak- ness (5), lethargy, dysphoria~and insomnia (2). A decrease in performance status following maytansine administration was considered to be predominantly due t0 central toxicity (2). These toxicities appeared to be distifiCt from peripheratnervous system toxicities and also were not related to metabolic or electrolytic abnormalities (5). It is of interest that these severe incapacitating central nervous system toxicities were not reported in the M; D. Anderson and Mayo Clinic studies when the total maytansine dose was divided into 3 daily administrations: The central nervous System and gaStrointestinal symptoms have been responsible for patients refusing further courses of therapy (5). Peripheral nervous~stem. Dose limiting vincristine-Hke peripheral neuropathies have been reported after treatment with maytansine by Blum et at. (2)- Patients complained.of jaw pain and parasthesia as well as severe myalgia. The loss of deep;itendort reflexes and marked prolongatign of ner-ce conduction times have also been noted. Patients with prior neuropathy either Secondary to malignancy or vincristine demonstrated, further, neurologic toxicity from maytansine~ Transient parasthesia for 24 h foll0wing~drug ad- ministration was als o reported by Chabneretal. (5) in 4 patientsand Gabanillas et al. (3) in a Phase II study reported parasthesia in 3 patients and~adynamic ileus, in 2 patients. ttepatic. Transient elevations ofserum transaminase, alkaline phosphatase and bilirubin Ievels have been reported in" allthe Phase I studies (2, 4-6); In patients without initial liver impairment these elevations returned to normal byDay 29. In tiie M, D. Anderson study 3 patients with prior abnormal hepatocellular function had rapid deterioration Of liver function following maytansine therapy and subsequently died. Howeverlhepatic toxicity was considered to be the cause Of death in only 1 patient (4). Myelosuflpression. Myelosuppression does:not appea r to be a dose limitixag toxicity of maytansine, Thrornbocytopenia was reported in less than 11% of courses in 2 Studies and was found predominantly in patients with liver function abnormality (4; 6), Phlebitis. Local minor phlebitis was reported i n two studies. In one study it was eliminated by diluting the druffin: larger volumes (250: to 500ml) of fluid: (4) and in the other by using rapid bolus injection (2).
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`MAYTANSINE CANCRR THERAPY 205 Table 2. Su~nun~ary of tmnors responsive to zr~yltax~lne TotAl cvaluable Improvement Tumor type patients CR PR < PR Duration of effect Reference Acute lymphoblastic 4 1 I I Adult with MI (5) leukemia rernhsion for 1 month-1 child with clearing of marrow and peripheral blasts for 3~ months Non-Hodgkins lymphoma 3 I 9 months (5) Ovary 5 1 5 months (5) Breast 25 I 2 Partial response (2-6) for 1 month Melanoma 27 ~ 2 Partial response (2-6) for 5+ months Head and neck 2 1 (2,4) (CR ---- Complete response; PR ----- Partial response = Tumor regression ~ 50%). Other. Other infrequently reported toxicities included moderate stomatitis and mild alopecia (4). Antltumor activity The cmnulative antitumor response reported in clinical studies is shown in Table 2. The responses in breast cancer and melanoma seen in their Phase I study (4) encouraged the M. D. Anderson group to conduct a Phase II study in these tumor types. However only 2 of 11 patients with melanoma had objective tumor regressions but these were less than 505/o, and no objective responses were seen in the 6 breast cancer patients in this study (3). The most encouraging antiturnor activity was seen in patients with acute lympho- Treble 3. Summary of ewaluable ¢uznor types without demnon- strable objective response to ~myt~aslne Number of evaluable Tumor type patients treated Reference Acute non-lyrnphoblastic S (5) leukemia Hodgkins Iymphoma 2 (5) Sarcoma 9 (2, 5,6, ) Colorectal 27 (2, 6) Stomach 2 (6) Panc~adc 2 (5, 6) Adenocaxcinoma 4 (4, 6) unknown priory Hep~toma 1 (5) Lu~cluding 1 12 (2, 4, 6) sl~ifi~"smal| ceil) Prostate 2 (6) Reml 2 (2, 4) Thymoma I (6)
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`206 B.F. ISSELL AND S. T. CROOKE blastic leukemia (ALL) where 2 of 4 patients responded including 1 complete remission and malignant lymphoma where 1 of 3 patients achieved a complete remission (5). These responses were seen in patients who had previously ` been treated with vincristine. One of the ALL patients was clearly clinically resistant to vincHstine and the patient with malignant lymphoma had failed therapy with VP-16and with a vincristine-containing combination. A summary of tumor types not demonstrating any objective response to maytansine therapy is shown in Table 3. In all of these tumors with thepossible exception ofcolorectal adenocarcinoma too" few patient.sat sufficiently high concentrations of drug have been evaluated to state that maytansine is inactive. The activity of maytansine in small cell lung cancer is of special interest because of the respor~siveness of this tumor to vincristine. However of the 12 evaluable lung cancer patients only I was specified as being of this histologic type. Summary and conclusions 1. Maytansine is an antitumor agent with antimitotic properties similar to the vinca alkaloids. Although its mechanism of action is similar to vincristine, preclinical studies suggest maytansine is more potent, and has an additional tubulin binding site. May° tansine may therefore be active in tumors resistant to the vinca alkaloids. 2. Of importance to the further clinical development of maytansine is the development of a quantitative assay with sufficient sensitivity to detect serum and tissue levels present at clinically tolerated doses. Present difficulties with drug supply will hope- fully be relieved by the development of a fermentation process which in turn may allow sufficient quantities of drug for the development of a radioimmunoassay. 3. The findings of central nervous system toxicity in both animal and human studies suggests that maytansin e may cross the blood-brain barrier and this should be clarified by the development of a quantitative assay to measure cerebrospinal fluid drug concentrations. Maytansine efficacy against brain tumors should be carefully evaluated in future studies. 4. The mairi dose limiting toxicities relate to the effects of maytansine on the gastro- intestinal'r.tra~t and nervous systems. The contribution of neurotoxicity to gastro- intestina~r~ox[city is difficult to evaluate. It is possible that the excretion ofmaytansine and/or i~'-~tabolites into thegastrointertinal tract via the hepatobiliary pathway may be directly responsible for much of the gastrointestinal effects. If so the thera- peutic manipulation to increase gastrointestinal transit at the time ofdrug administra- tion or the prescribing of substances by mouth whichwill preferentially bind the drug and its toxic products in the gastrointestinal tract are potential methods for relieving gastrointestinal toxicity. An assay to measure fecaldrug concentrations will help answer, these questions. 5. The central nervous system toxicities which have been responsible for patients refusing further therapy in some instances are possible related to peak serum levels. This is sug- gested by these toxicities being reported only in studies in which the total maytansine dose was given as a single administration. CleaHy further investigation is required to determine the optimal therapeutic index and the development of a drug assay will .help achieve this objective,
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`MAYTANSINE CANCER THERAPY 207 . . The administration of maytansine, like vincristine is associated with peripheral neuropathy. This may be cumulative and will need to be carefully evaluated in the future. Antitumor activity has been demonstrated in lymphoblastic leukemia and malignant lyrnphoma; malignancies which are also responsive to vincristine. The clinical data suggest that maytansine is active in these tumors after the development of vincristine resistance and should encourage a more thorough evaluation of this drug in malig- nancies of lymphoid origin. A careful evaluation of maytansine in small cell lung cancer, another vincristine responsive tumor, should also be undertaken. Acknowledgement The authors wish to thank Ms Carol Boyd for typing this manuscript. References 1. Alabaster, O. & Cassidy, M. (1978) J. natl. Cancer Inst. 60: 649-652. 2. Blum, R. H. & Kahlert, T. (1978) Canter Treat. Rep. 62: 435-438. 3. CabaniUas, F., Rodriguez, V. & Bodey, G. P. (1978) Proc. AACR[ASCO 19-. 102. 4; Cabanillas, F., Rodriguez, V., Hall, S. W., Burgess, M. A., Bodey, G. P. & Freireich, E.J. (1978) Canc~ Treat. Rep. 62." 425"428, 5. Chabner, B. A., Levine, A. S., Johnson, B. L. & Young, R. 13. (1978) Cancer Treat. Rep. 62: 429--433. 6. Eagan, R. T.. Ingle, J. N., Robln,J, Frytak, S. & Moertel, (3, G. (1978) J. natl. CancerIrtrt. 60:93-96 7. Hanka, L.J. & Barnett, M. S. (1974) Antimicrob. Ag. Chemother. 6: 651-652. 8, Hartmann, G., Hanikel, K. O., Knusel, F. & Nuesch, J. (1967) Biochem. Biopkys. Acta 145: 843. 9. Helman, L., Henney, J. & Slavik, M. (1976) Maytansine (NSC 1.53858) Clinical Brochure. Investigational Drug Branch, Division of Cancer Treatment, National Cancer Institute. 10. Higashide, E., Asai, M., Ootsu, K., Tanida, S., Kozai, Y., Hasegawa, T., Kishi, T., Sugino, Y. & Yonaa, M, (I 977) Nature 270-. 721-722. 11. Kupchan, S. M. (1974) Fed. Proc. 33: 2288"-2295. 12. Kupdaan, S. M., Komoda, Y., Branfman, A. R.,Dailey, R. G. & Zimmerly, V. A. (1974) J. Am. Chem. Soc. 96: 3706-3708. 18. Kupchan, S. M., ?,Kornoda, Y~, Court, W. A., Tomas, G.J., Smith, R. M., Karim A., Gilh-nore, C.J., Haltiwanger, R. C. &Bryan, R. F. (1972! a r. Am. Chem. Soc. 94~ 1354--!556. 14. Kupchan, S. M., Sned ens A. T., Branfman, A. R. & Howie, G, A. (1518)J. Med. Chem. 21:$1-37 15. Mandelbaun-Shavlt, F., Wolpert-DeFillippea, M. K, & Johns, D. G. (1976) Biodmn. Biophys. Rex. Conunun. 72: 47-54: 16. Mandelbaun-Shavit, ~,Volpert-DeFLllippes, M. K.,Johns, D~ Gc (1976)Fed. Proc. 35: 786. 17. Mizuno, S., Yamazak i, H., Nitta, K. & Unc~twa, _.H. (i968) Biochem, Biophys. Acta 157: 322, 18. Mugera, G, M. & Ward, G.M. (1977) Cancer Treat ~ Rep~ 61: 1833"1338. 19. Rea'nillard, S. & Rebhun, L. L (1975)Sciente-189:lO02,,lO05. 20. Sehaitman, T., Rebhun, L. I., and KuPchan, S. M.-(1975) Or. Cell Biol. 67: 388a. 21. Sieber, S. M., Wolpert, M.IK.; Adamson, R.H;, Cysyk, R. L., Bono, V. H. & Johm, D. G. (1976) G oraparative Leukemia Research 1975, Bibl. Heamat. 43: 495-.500. 22. Wolpert'DeFillippes, M; K., Adamson, R~ H., Cysyk, R;L., and Johns, D. G, (1975) Biochem. Pharma¢ol. 24:751"754. 23. Wolpert-DeFillippes, M, K., Bono, V. H., Dion. R. L. & Johns, D. G. (t975)Bioehem. Pharma¢ol. 24: 1735-1738.
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