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`Critical Reviews in Oncology/Hematology, 1991; 11:43-64
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`:0 1991 Elsevier Science Publishers B.V. 1040-8428/91/$3.50
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`ONCHEM 00003
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`43
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`New anthracycline antitumor antibiotics
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`Franco M, Muggia i and Michael D. Green2
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`J Department of Medicine, University of Southern California, Los Angeles, CA and 1 Department
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`of Medical Oncology and Haematology, Parkville. Victoria, Australia
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`Contents
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`L Abstract ..
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`II. Introduction ....................................................................... .
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`II L Overview of anthracycline drug development . . . . . . . . . . . . . . . . . . . . . . . .
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`A. Historical background. . . . . . . . . . . . . . . . . . .
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`B. General concepts .............. .
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`C. Specific research areas .......... .
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`I. Expanding therapeutic spectrum
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`2. Attenuating toxicities ....... .
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`3. Favorable pharmacology ... .
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`D. Differentiating properties ....... .
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`E. Intrinsic and acquired resistance ."
`F. Cardioprotection .............. .
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`[v. New findings with DX ............ .
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`A. Therapeutic targets ................. .
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`I. Breast cancer. . . . . . . . . . . . . . . . . . .
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`2. Malignant lymphomas and Hodgkin's disease (HD) ............................ .
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`3. Childhood and adult leukemias. . . . . . . . . . . . . . . . . . . . . . . .
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`4. Childhood solid tumors ...
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`5. Adult soft tissue and bone sarcomas ...
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`6. Kaposi's sarcoma (KS) .... .
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`7. Gynecologic cancer ........ .
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`8. Genitourinary cancer. . . . . . .
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`9. Major gastrointestinal cancer .................................. .
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`10. Hepatobiliary carcinoma and rare gastrointestinal neoplasms ..... .
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`II. Lung cancer and upper and lower aerodigestive tracts ........... .
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`12. Miscellaneous tumors .......................................... .
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`B. Synergy and resistance ......... .
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`C. Pharmacologic considerations ... .
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`D. Modulation of toxicity ............... .
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`FM. Muggia received a B.S. degree from Yale University, New
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`Haven, CT and a M.D. degree from Cornell University, New York,
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`NY. Dr. Muggia is currently the Professor of Medicine at the Univer(cid:173)
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`sity of Southern California, Los Angeles, CA. M.D. Green received a
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`M.D. degree from the University of Melbourne, Melborne, Australia.
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`Dr. Green is currently the Deputy Director in the Department of
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`Medical Oncology and Haematology. Royal Melborne Hospital, Mel(cid:173)
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`bourne, Australia.
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`Correspondence: F.M. Muggia, Department of Medicine, University
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`of Southern California, 1441 Eastlake Avenue, Los Angeles CA
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`90033, U.S.A.
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`NOVARTIS EXHIBIT 2057
`Breckenridge v. Novartis, IPR 2017-01592
`Page 1 of 22
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`V. Clinical trials with newanthracyclines .............. .
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`A. Epirubicin
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`B. 4-Demethyoxydaunorubicin (idarubicin) ....
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`C. THP-doxorubicin ..... .
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`D. Aclacinomycin A
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`E. Carminomycin (CMM).
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`F. 4' Deoxydoxorubicin (esorubicin)
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`G. Menogaril ..
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`VI. Conclusions and future prospects.
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`References
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`I. Abstract
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`Doxorubicin is an essential component of the treat(cid:173)
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`ment of aggressive lymphoma, childhood solid tumors,
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`bone and soft tissue sarcomas, and breast cancer and
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`additional indications are emerging. On the other hand,
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`daunorubicin has occupied the central position of inter(cid:173)
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`est in the treatment of acute leukemia. Epirubicin has a
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`spectrum very similar to doxorubicin but lesser toxicity.
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`The ability to protect against cardiotoxicity with ICRF-
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`187 further enhances clinical interest in exploiting modi(cid:173)
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`fications in doze intensity to therapeutic advantage. Ida(cid:173)
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`rubicin has at least equivalent activity to daunorubicin
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`and doxorubicin in leukemia.
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`New areas of research in relation to anthracycline an(cid:173)
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`tibiotics include introduction of new the analogs, insight
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`into mechanisms of resistance, the reversal of multidrug
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`resistance in vitro, the protection of cardiac toxicity,
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`and the study of other important biochemical reactions
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`relevant to cytotoxicity.
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`Orally active anthracyclines such as idarubicin and
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`compounds which lack cross-resistance with the parent
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`drugs or have other mechanisms for cytotoxicity are
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`lead to an expanding therapeutic spectrum for these al(cid:173)
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`ready widely useful drugs.
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`II. Introduction
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`This review updates the status of anthracycline re(cid:173)
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`search concentrating on the clinical prospects of drugs
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`that have been introduced following the first decade of
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`clinical anthracycline studies (1965-1975). The interest
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`generated by daunorubicin and doxorubicin in cancer
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`treatment has been documented in several previous
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`comprehensive overviews, and also in proceedings of
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`scientific meetings which have coupled advances in basic
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`and clinical knowledge on anthracyclines as anticancer
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`drugs [1-8]. A recent volume edited by J. William Lown
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`covers in detail the following aspects: (i) isolation, syn(cid:173)
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`thesis and properties, (ii) biophysical studies related to
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`mechanisms of action, and (iii) pharmacology, toxicity
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`and clinical aspects of these compounds and the synthet(cid:173)
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`ic anthracenediones. For the clinician desiring a per(cid:173)
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`spective on new anthracycline antibiotics, we shall focus
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`on new compounds which are in clinical trial. while also
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`summarizing important new directions in anthracycline
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`research. Accordingly we shall begin with an overview
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`of anthracycline drug development in order to provide
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`the appropriate background and the rationale for the in(cid:173)
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`terest generated by these drugs; continue with a summa(cid:173)
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`ry of new findings still being acquired with the parent
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`compounds in the clinic, and then proceed to an individ(cid:173)
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`ual description of each new agent. This sequence logi(cid:173)
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`cally leads to an appraisal of future prospects in cancer
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`treatment.
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`III. Overview of anthracycline drug development
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`Ill-A. Historical Background
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`Anthracycline antibiotics were isolated and studied in
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`various pharmaceutical laboratories since the late 1950s
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`and early 1960s. Most prominent in this effort were the
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`group at the Farmitalia Research Laboratories in Mi(cid:173)
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`lano headed by Aramone and DiMarco [9] and the Par(cid:173)
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`isian group of the Rhone-Poulenc Laboratories whose
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`anthracycline research was developed by Dubost et al.
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`[10]. The Italian group first embarked in clinical studies
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`with 'daunomycin' and subsequently its C-14 hydroxy
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`derivative 'adriamycin', whereas the French concomi(cid:173)
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`tantly initiated clinical studies with
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`These drugs were soon renamed 'daunorubicin' (upon
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`demonstration of the chemical identity of daunomycin
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`and rubidomycin) and 'doxorubicin'. Interest in other
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`laboratories followed quickly with new related chemical
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`structures being studied in the United States, Germany,
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`the Soviet Union and Japan [II]. Some of these com-
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`NOVARTIS EXHIBIT 2057
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`Page 2 of 22
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`pounds differed substantially in structure and in toxico(cid:173)
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`logic properties, and were eventually introduced into
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`clinical trial (see Section V).
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`The initial clinical studies with daunorubicin both in
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`France and the United States provided the impetus for
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`further interest in anthracycline drug development: im(cid:173)
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`pressive activity was noted against acute leukemia and
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`childhood solid tumors, but a vast array of toxicities in(cid:173)
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`cluding marrow hypoplasia, total alopecia, extravasa(cid:173)
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`tion necrosis and a peculiar cardiomyopathy became ev(cid:173)
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`ident [12,13]. Trials with doxorubicin, in large part
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`sponsored by the National Cancer Institute (NCI,
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`U.S.A.) began to demonstrate impressive activity in
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`breast cancer, ovarian cancer, malignant lymphomas,
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`small cell lung cancer, germ cell tumors and sarcomas
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`in addition to the areas where daunorubicin already had
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`established efficacy [I]. The success of doxorubicin
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`blunted further development of daunorubicin [14] and
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`also of second generation derivatives such as rubidazone
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`Groups at Farmitalia and at Stanford Research Insti(cid:173)
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`tute became particularly active in structure-activity rela(cid:173)
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`tionships and dissected out important toxicologic fea(cid:173)
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`tures and determinants of potency [16,17]. Several of
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`these compounds, which are derivatives of doxorubicin
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`(OX) or daunorubicin (DNR) have been readied for
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`clinical trial and will be covered in Section V. Only pre(cid:173)
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`clinical data is currently available for other compounds
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`which are targeted for clinical development such as the
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`3'.3-cyano-4-morpholinyl derivatives, with their unique
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`lOOO-times potency relative to OX [17,18].
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`Anthracycline drug development also became estab(cid:173)
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`lished at the Institute of Microbial Chemistry in Tokyo,
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`where the trisaccharide aclacinomycin was the first read(cid:173)
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`ied for clinical trial [19]. Biochemical effects on nucleo(cid:173)
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`lar RNA synthesis of this drug and others isolated by
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`Bristol Myers (e.g., marcellomycin, musettamycin) were
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`distinct enough from DX and DNR that a classification
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`evolved in Type I and Type II anthracyclines depending
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`on their effects on RNA vs. DNA synthesis inhibition
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`[20]. At the Upjohn Company, derivatives of another
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`anthraquinone, nogalomycin, were studied [21] and in
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`1984 they introduced menogaril into clinical trial. Addi(cid:173)
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`tional drugs tested included a compound developed by
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`Israel at the Dana Farber Cancer Institute (AD-32) [22];
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`this compound and other water soluble derivatives are
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`being considered for subsequent clinical trial. More re(cid:173)
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`cently, other derivatives closely related to doxorubicin:
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`THP-adriamycin (THP-DX) and detorubicin were in(cid:173)
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`troduced in Japan and France, respectively [23,24].
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`Finally, there have been many attempts at developing
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`carriers for several of the anthracyclines. These carriers
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`have included calf thymus DNA [25], ferrous iron [26],
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`amino acids [27], various types of Ii po somes [28], neutral
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`phosphalipids [29] and conjugates with monoclonal
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`antibodies [30]. Such attempts to improve targeting and
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`attenuate toxicity have met with varying degrees of suc(cid:173)
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`cess. Ultimately, they have not become established
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`treatment methods because practical issues have not
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`been resolved. While searches for better and less toxic
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`analogs have continued, increasing knowledge about
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`mechanisms of action has led to important therapeutic
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`concepts of drug synergy and resistance, and has stimu(cid:173)
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`lated efforts on other methods of protecting against tox(cid:173)
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`icities of established anthracyclines. These will he de(cid:173)
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`scribed further in the next heading. Table I and Fig. I
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`indicate the structures that have heen developed for clin(cid:173)
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`ical study.
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`III-B. General concepts
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`Table 2 summarizes biological effects and biochemi(cid:173)
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`cal targets of anthracycline antibiotics. Based on effects
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`on DNA vs. RNA synthesis inhibition the classification
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`proposed by DuVernay and Crooke introduced the terms
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`Type I and Type II anthracyclines [20]. Such classifica(cid:173)
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`tion usually separates monosaccharides from di- and
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`trisaccharides, and does not address the multitude of
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`other biochemical mechanisms associated with anthra(cid:173)
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`cycline action. New compounds are introduced with
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`specific properties in mind. For example, 4-iminoDNR
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`lacks a quinone moiety which precludes free radical acti(cid:173)
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`vation [28]. Cyanomorpholynyl derivatives are conside(cid:173)
`
`
`
`
`
`
`
`rably more potent than parent compounds, bind irrever(cid:173)
`
`
`
`
`
`
`
`
`
`
`sibly to DNA, and show a lack of crossresistance [18].
`
`
`
`
`
`
`
`
`
`Changes in the 4' position have been exploited by Arca(cid:173)
`
`
`
`
`
`
`
`
`mone and co-workers at Farmitalia Carlo Erba [16].
`
`
`
`
`
`
`
`
`
`
`The stereoisomer of DX by an inversion at the C-4' posi(cid:173)
`
`
`
`
`
`
`
`
`
`tion has resulted in the 4'-epi derivative with attenuated
`
`
`
`
`
`
`
`toxicity and allowing unique glucuronide formation as
`
`
`
`
`
`
`
`a metabolite. The 4'-deoxy derivative (esorubicin) was
`
`
`
`
`
`
`
`introduced because of even greater attenuation in toxi-
`
`
`
`TABLE I
`
`
`
`
`Clinically treated anthracyclines
`
`
`
`Idarubicin (4-demethoxydaunorubic'in)
`
`
`Epirubicin (4'-epidoxorubicin)
`
`
`Esorubicin (4'-deoxydoxorubicin)
`
`
`
`4' iodo-4' deoxydoxoruhicin
`
`Rubidazone
`
`
`
`Carminomycin (4-demethyldaunorubicin)
`
`
`
`THP-Adriamycin (4'-O-tetrahydropyranyl doxorubicin)
`
`AD-.'l::!
`
`
`Adacinomycin A
`
`Detorubicin
`
`Mcnogaril
`
`NOVARTIS EXHIBIT 2057
`Breckenridge v. Novartis, IPR 2017-01592
`Page 3 of 22
`
`
`
`
`46
`
`o
`
`
`
`OH
`
`10
`
`COCH3 <dauno)
`~ ~ ggg~~g~ ~toD~2)
`CNNHCOOCH3
`(rubidazone)
`
`
`TABLE 2
`
`
`
`
`
`
`
`
`
`
`Biological and biochemical effects of anthracyclines binding to DNA
`
`o
`
`
`
`• NH (imino)
`
`
`
`
`OH
`
`
`H
`
`
`
`
`
`Inhibition of topoisomerase II
`
`
`
`
`Inhibition of DNA polymerases
`
`
`
`
`Induction of DNA breaks
`
`
`
`Free radical generation
`
`
`
`Cell membrane disruption
`
`
`
`Ion exchange alterations
`
`
`
`
`Binding to phospholipids, calmodulin
`
`
`
`
`
`
`
`
`wide variety of research directions, some representing
`
`
`
`
`
`
`
`
`general trends in analog development and others which
`
`
`
`
`
`
`
`
`are unique to the anthracyclines. Section IV includes
`
`
`
`
`
`
`
`
`
`newer trends in the use of doxorubicin, whereas Section
`
`
`
`
`
`
`
`
`
`V deals with some findings with analogs which have al(cid:173)
`
`
`
`
`
`
`ready become established in the clinic.
`
`III-C. 1. Expanding therapeutic spectrum
`
`
`
`
`
`
`
`
`
`
`
`
`
`More active drugs are always desirable, but often un(cid:173)
`
`
`
`
`
`
`
`
`
`attainable as the first discovered compound is often the
`
`
`
`
`
`
`
`
`most strikingly active of the series. More potent com(cid:173)
`
`
`
`
`
`
`
`
`
`pounds have been commonly identified but this does not
`
`
`
`
`
`
`necessarily indicate better antitumor activity. Com(cid:173)
`
`
`
`
`
`
`
`
`pounds which might be more effective against leukemia
`
`
`
`
`
`
`such as 4-demethoxyONR (idarubicin) provide valuable
`
`
`
`
`
`
`
`
`clues with regards to selectivity of anthracyclines. In
`
`
`
`
`
`
`
`
`
`leukemia, DNR and its derivatives are at least equally
`
`
`
`
`
`
`
`
`
`
`
`
`active if not better than DX [38]. It remains to be seen
`
`
`
`
`
`
`
`
`whether drugs with very different mechanisms of action
`
`
`
`
`
`
`will have an altered therapeutic spectrum. Aclacinomy(cid:173)
`
`
`
`
`
`
`
`cin's activity appeared confined to leukemia, whereas
`
`
`
`
`
`
`
`
`
`little is known on selectivity of compounds such as cya(cid:173)
`
`
`
`
`
`nomorpholino derivatives. Selectivity towards colon
`
`
`
`
`
`
`
`cancer was claimed for esorubicin [39], however, subse(cid:173)
`
`
`
`
`quent trials were disappointing.
`
`III-C. 2. Attenuating toxicities
`
`
`
`
`
`
`
`
`
`
`Subjective tolerance may be improved in anthracy(cid:173)
`
`
`
`
`
`
`
`
`clines that are prod rugs of the parent compounds, pre(cid:173)
`
`
`
`
`
`
`
`
`
`sumably because these are equivalent in part to slow re(cid:173)
`
`
`
`
`
`
`
`
`
`lease forms. For example, rubidazone may be less toxic
`
`
`
`
`
`
`
`
`
`
`than DNR, and THP-OX has been claimed to be less
`
`
`
`
`
`
`
`
`
`toxic than DX. Subjective tolerance is often reflected by
`
`
`
`
`
`
`
`diminished nausea and vomiting, lesser stomatitis, lesser
`
`
`
`
`
`
`alopecia and more consistent myelosuppression as dose(cid:173)
`
`
`
`
`
`
`
`
`limiting toxicity. Claims have been made for menogaril,
`
`
`
`
`
`
`
`THP-DX, aclacinomycin, and AD-32 in causing less
`
`
`
`
`
`
`
`
`
`alopecia [40]; epirubicin was also milder in all these as(cid:173)
`
`
`
`
`
`
`
`
`
`pects, but also may have less myelosuppression than DX
`
`
`
`
`
`
`
`
`
`
`at doses which are believed to be equivalent in efficacy
`
`[41].
`
`
`
`
`
`
`
`
`
`A specific effort has been made to attenuate the car-
`
`
`4' halyl
`
`
`
`
`
`
`
`3'
`
`
`
`
`invertec:.~~y ~:i~) ... 4'
`
`
`OH
`disaccharides (el.sall) NH .2
`
`
`~~:aanhy'id(~HP) ~
`
`
`
`
`N~triflouroacetyl <AD 32)
`(class II>
`(CH3)2
`
`
`
`
`cyanomorphilinyl
`
`
`
`
`
`
`
`
`
`
`
`Fig. I. Structure of anthracyclines with identification of major analog
`
`
`
`
`
`
`classes in relation to chemical substituents.
`
`
`
`
`
`
`
`
`
`city [6]. Although clinical studies have not indicated suf(cid:173)
`
`
`
`
`
`
`
`
`
`ficient activity for this last compound, the addition of
`
`
`
`
`
`
`
`
`
`
`halogens at the 4' position (4' iodo 4' deoxyDX) results
`
`
`
`
`
`
`
`
`in enhanced potency, oral activity and activity against
`
`
`
`
`P388 OX-resistant leukemia [18,31].
`
`
`
`
`
`
`
`
`
`Replacement of the methoxy group in the 4 position
`
`
`
`
`
`
`(4-demethoxy derivatives) have yielded idarubicin which
`
`
`
`
`
`
`
`
`
`is active orally and appears of interest in leukemia (Sec(cid:173)
`
`
`
`
`
`
`
`tion IV) [32]. Carminomycin is a demethoxy anthracyc(cid:173)
`
`
`
`
`
`
`
`
`
`line which is considerably more potent than DX or
`
`
`
`
`
`
`
`
`DNR but with lesser activity [5]. Additional compounds
`
`
`
`
`
`
`
`containing 6-deoxy and ll-deoxy modifications will
`
`
`
`
`
`
`lead to further information on structure-activity rela(cid:173)
`
`
`tionships [18].
`
`
`
`
`
`
`
`
`
`A-ring side arm changes were among the first being
`
`
`
`
`
`
`
`
`
`
`explored (in fact OX is the first such derivative ofDNR)
`
`
`
`
`
`
`
`[15]. Other side chain derivatives include rubidazone,
`
`
`
`
`
`
`
`
`detorubicin and AD-32, the latter also having an N-tri(cid:173)
`
`
`
`
`
`
`
`fluoroacetyllinked to the amino sugar [33-36].
`
`
`
`
`
`
`
`
`
`This last modification is shared by other AD series
`
`
`
`
`
`
`
`compounds synthesized by Israel which have lesser po(cid:173)
`
`
`
`
`
`
`
`
`
`
`tency and toxicity, and do not appear to intercalate in
`
`
`
`
`
`
`
`
`the nucleus [33-36]. A different chromophore that in ad(cid:173)
`
`
`
`
`
`
`
`
`
`dition has a sugar originating in the D-ring rather than
`
`
`
`
`
`
`
`
`
`in the A-ring is menogaril [21]. This compound has
`
`
`
`
`
`
`
`
`shown attenuated toxicities and is in clinical trial (Sec(cid:173)
`
`
`tion V).
`
`
`
`
`
`
`
`
`Differential action on the immune system is yet an(cid:173)
`
`
`
`
`
`
`
`other property on which to base structure-activity rela(cid:173)
`
`
`
`
`
`
`
`
`tionships [37]. However, the contribution of such effects
`
`
`
`
`
`
`
`on the ultimate antitumor action is uncertain.
`
`III-C. Specific research areas
`
`
`
`
`
`
`
`
`
`
`
`
`
`The diversity of anthracycline actions has spawned a
`
`NOVARTIS EXHIBIT 2057
`Breckenridge v. Novartis, IPR 2017-01592
`Page 4 of 22
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`
`
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`diotoxicity of these drugs by utilizing animal screens
`
`
`
`
`
`
`
`
`
`[42]. Some claims were later not substantiated in clinical
`
`
`
`
`
`
`
`
`studies (e.g., the lack of cardiotoxicity of carminomycin
`
`
`
`
`
`
`
`
`and of esorubicin). Clinical experience has validated the
`
`
`
`
`
`
`
`lesser cardiotoxicity of epirubicin which is presumably
`
`
`
`
`
`
`
`
`related to its more favorable pharmacology. Based on
`
`
`
`
`
`
`
`clinical findings to date, menogaril appears less cardio(cid:173)
`
`
`
`
`
`
`
`
`
`
`toxic, and similar claims have been made for AD-32 and
`
`
`
`
`
`
`
`
`THP-DX from preliminary phase I data. (Section V and
`
`
`its references.)
`
`
`
`
`
`
`
`
`Aclacinomycin trials and results of phase I studies
`
`
`
`
`
`
`
`with marcellomycin have suggested a different toxicity
`
`
`
`
`
`
`spectrum for these trisaccharides: considerable nausea
`
`
`
`
`
`
`and vomiting, more erratic and delayed myelosuppres(cid:173)
`
`
`
`
`
`
`
`
`
`
`sion, and a tendency to give rise to acute arrhythmias
`
`
`
`
`
`even though cardiomyopathy and extravasation necro(cid:173)
`
`
`
`
`
`
`
`
`sis were absent. Preclinical studies in Japan had sug(cid:173)
`
`
`
`
`
`
`
`
`gested that aclacinomycin was not mutagenic in systems
`
`
`
`
`
`
`
`
`
`where DX was very mutagenic. Such finding had been
`
`
`
`
`
`
`
`considered a rationale for further testing, including ad(cid:173)
`
`
`
`
`
`
`
`juvant situations, but unfortunately efficacy was found
`
`
`
`
`wanting in solid tumors.
`
`
`
`
`
`
`
`In summary, attenuated toxicities are a justification
`
`
`
`
`
`
`
`
`
`
`for the development of some of these analogs. With the
`
`
`
`
`
`
`exception of epirubicin, however, the antitumor spec(cid:173)
`
`
`
`
`
`
`
`
`
`trum of most analogs is substantially different from DX.
`
`
`
`
`
`
`
`
`Therefore, one cannot consider such analogs merely as
`
`
`
`
`
`
`
`
`
`less toxic DXs, but other circumstances for their use
`
`
`
`
`
`
`
`may be found. For example, intraperitoneal therapy
`
`
`
`
`
`
`
`with AD-32 and aclacinomycin may be considered ap(cid:173)
`
`
`
`
`
`
`
`
`
`
`
`propriate, whreas DX is too toxic via this route. In some
`
`
`
`
`
`
`
`
`
`
`instances not only is lesser efficacy a problem with these
`
`
`
`
`
`
`
`analogs, but new toxicities appear. Several compounds
`
`
`
`
`
`
`have local toxicities rendering peripheral vein adminis(cid:173)
`
`
`
`
`
`tration problematic (e.g., esorubicin, AD-32, menoga(cid:173)
`
`rill·
`
`III-C. 3. Favorable pharmacology
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Activity via the oral route may be a useful property
`
`
`
`
`
`
`
`with obvious advantages in patients with childhood
`
`
`
`
`
`
`
`leukemias and in breast cancer where compromised ve(cid:173)
`
`
`
`
`
`
`
`
`
`nous access is common. However, when oral trials have
`
`
`
`
`
`
`
`
`
`been performed, they have so far been accompanied by
`
`
`
`
`
`
`
`
`slightly more variable bioavailability and also by some
`
`
`
`
`
`
`gastrointestinal intolerance. Nevertheless, the oral route
`
`
`
`
`
`
`
`
`is being explored further with idarubicin and menogaril.
`
`
`
`
`
`
`
`
`This latter drug causes phlebitis so that oral administra(cid:173)
`
`
`
`
`tion may prove advantageous.
`
`
`
`
`
`
`
`
`A vast amount of information is accumulating on
`
`
`
`
`
`comparative pharmacokinetics of anthracyclines [43].
`
`
`
`
`
`
`
`
`Tissue distribution may account for the relative lesser
`
`
`
`
`
`
`
`toxicity claimed for THP-DX. Similarly, tissue and in(cid:173)
`
`
`
`
`
`
`
`tracellular distribution is vastly changed with AD-32
`
`
`47
`
`
`
`
`
`
`
`
`
`and its derivatives. The lipophilicity of AD-32 required
`
`
`
`
`
`
`
`
`special solvents and 24 h infusion schedules. Liposomal
`
`
`
`
`
`
`
`
`carriers also greatly change the tissue distribution and
`
`
`
`
`
`
`may alter the toxicology of anthracyclines.
`
`
`
`
`
`Metabolic degradation has common threads: biore(cid:173)
`
`
`
`
`
`
`
`ductive production of alcohols being the most impor(cid:173)
`
`
`
`
`
`
`
`
`
`
`tant followed by a variety of sugar ring cleavages [44].
`
`
`
`
`
`
`
`
`Such reductive products are generally less active than
`
`
`
`
`
`
`
`
`
`
`the parent compound, but in the case of idarubicin, the
`
`
`
`
`
`
`
`
`13-(S)-alcohol derivative is actually more active and has
`
`
`
`
`
`
`
`
`
`
`
`a longer half-life [18]. The ratios of alcohol derivative to
`
`
`
`
`
`
`parent compound may be increased with oral adminis(cid:173)
`
`
`
`
`
`tration for this drug.
`
`
`
`
`
`
`
`
`
`Of great interest was the discovery of glucuronides as
`
`
`
`
`
`
`
`products of epirubicin metabolism. This stereoisomer of
`
`
`
`
`
`
`
`
`DX is more extensively metabolized and may account
`
`
`
`
`
`
`
`for its better tolerance. This pharmacologic property
`
`
`
`
`
`
`
`
`
`may also render it more suitable than DX for combina(cid:173)
`
`
`
`
`
`
`
`
`
`tions with a cardioprotective agent (see item F, this sec(cid:173)
`
`
`
`
`
`
`
`
`tion). Glucuronide formation is a unique property of
`
`
`
`
`
`
`
`human metabolism, not having been identified in pre(cid:173)
`
`
`clinical studies.
`
`III-D. Differentiating properties
`
`
`
`
`
`
`
`
`
`Some evidence that anthracyclines promote differen(cid:173)
`
`
`
`
`
`
`
`
`
`tiation has been acccrued, and it has stimulated interest
`
`
`
`
`
`
`
`in possible clinical implications. Studies have dealt
`
`
`
`
`
`
`
`
`primarily with Friends murine leukemia model and the
`
`
`
`
`
`
`
`human promyelocytic leukemia HL-60 [45]. Both in
`
`
`
`
`
`
`
`
`vitro and in vivo studies indicate varying contributions
`
`
`
`
`
`to differentiation among anthracyclines. Noteworthy
`
`
`
`
`
`
`
`
`has been the activity of marcellomycin in inducing dif(cid:173)
`
`
`
`
`
`
`
`ferentiation in the various systems studies. However,
`
`
`
`
`
`
`
`
`
`
`
`more remains to be learned on how this action may be
`
`
`
`
`
`
`exploited. Combinations of anthracyclines with low
`
`
`
`
`
`
`
`dose cytosine arabinoside in myelodysplastic states are
`
`
`
`
`
`
`
`considered worth testing. The effect of 'differentiating'
`
`
`
`
`
`
`
`
`
`
`agents in solid tumor treatment is just beginning to be
`
`
`
`
`
`
`
`explored with several drugs in clinical trial. Anthracy(cid:173)
`
`
`
`
`
`
`
`
`
`clines may have actions on DNA and RNA synthesis
`
`
`
`
`
`
`
`
`
`which will prove useful in achieving such effects alone
`
`
`
`
`
`
`
`
`or in combination. At present, phenomena of teratoma
`
`
`
`
`
`derivation from embryonal cancers, and ganglioneuro(cid:173)
`
`
`
`
`
`
`
`
`mas from neuroblastoma appear related in part to bio(cid:173)
`
`
`
`
`chemical effects of drugs.
`
`III-E. Intrinsic and acquired resistance
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Drug resistance to antracyclines has been the central
`focus of much research since the laboratory discovery
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of multidrug resistance (mdr) to natural products [46].
`
`
`
`
`
`
`
`
`Clinical counterparts of this phenomenon are not diffi-
`
`NOVARTIS EXHIBIT 2057
`Breckenridge v. Novartis, IPR 2017-01592
`Page 5 of 22
`
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`48
`
`
`
`
`
`
`
`
`
`cult to conceive: the increasing refractoriness of solid tu(cid:173)
`mors following initial treatment, the lack of activity of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`most drugs in previously treated ovarian cancer, or the
`
`
`
`
`
`
`
`
`
`
`intrinsic resistance of colon cancer to a wide variety of
`
`
`
`
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`chemotherapeutic agents. Availability of reagents which
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`are able to detect amplification of the mdrJ gene or its
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`increased expression by determination of mRNA or its
`protein product (the membrane-bound p 170 glycopro(cid:173)
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`tein) will delineate the role of multi drug resistance in de(cid:173)
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`termining the antitumor spectrum of drug, and changes
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`that occur with tumor progression or exposure to prior
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`cytotoxic interventions [47]. Amplification of mdrI ap(cid:173)
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`pears to be a relatively uncommon but definite occur(cid:173)
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`rence in untreated sarcomas and in ovarian cancer.
`The mdr phenomenon and drug resistance concepts in
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`general are having a remarkable impact on drug devel(cid:173)
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`opment. Attention to resistance patterns has become
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`part of the study of any new anthracycline. Since mdr
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`is believed to be mediated by mechanisms involved in
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`the efflux of the drug, it is anticipated that enhancement
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`in mdrI gene activity will lead to cross resistance with
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`drugs of the same family. The absence of cross resist(cid:173)
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`ance of the potent cyanomorpholino derivatives is there(cid:173)
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`fore of interest, and may be related to the ability of this
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`derivative to bind irreversibly to DNA once it enters the
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`cell [17,18].
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`Other mechanisms of resistance must be implicated in
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`anyone case since resistance patterns vary widely
`among the natural products tested (e.g., actinomycins,
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`anthracyclines, colchicine, vinca alkaloids, etc.). Factors
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`such as DNA repair, nuclear localization and active
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`transpo