Introduction
The need for the development of new anticancer drugs is evident and of great importance for the future. Today cancer chemotherapy depends on a rather small panel of compounds from which a major part are in clinical use since more than 20 years. With the enormous body of knowledge which has been accumulated in chemistry, cell and molecular biology in the last few years it has become possible to develop novel molecules which, for example, exert their cytotoxic actions on cell membranes and on signal transduction pathways. It is more and more being recognized that the function of a cell membrane is not merely that of confining a cell, but that very important and complex mechanisms for cell regulation are closely linked to membranes. Thus, lipophilic molecules which interact predominantly with cellular lipid membranes are gaining increased importance as therapeutic agents.
The high efficacy of NOAC, coupled with its new mechanism of action, the uncomplicated and cheap chemical synthesis, the long-term stability of the lyophilized liposome formulation, together with a solid proprietary position render NOAC an exceptionally promising candidate of a parenterally and orally active antitumor drug with significant cytostatic effects in leukemias as well as in solid tumors, constituting an unique opportunity which warrants further exploration of this novel small antitumor molecule.
Major Properties of NOAC
The drug
The novel compound N4-octadecyl-1-beta-D-arabinofuranosyl cytosine (NOAC, Alkasar-18) is a lipophilic cytotoxic drug which was chemically derived from cytosine arabinoside (ara-C). NOAC has a molecular mass of 497.5 Daltons. NOAC has the NCI/NSC number: 685096
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Due to the alkyl chain which is attached at the N4-position of the cytosine moiety of cytosine arabinoside, NOAC is highly resistant against chemical and enzymatic deamination and as a consequence the cellular pharmacology, pharmacokinetics and mechanisms of action of NOAC are significantly different from those of ara-C.
Chemical Properties:
NOAC is prepared at high yields and excellent purity in four steps, starting from uridine which is a cheap natural ribonucleoside.
Pharmaceutical Formulation:
NOAC is formulated as a lyophilized preparation of small unilamellar liposomes of 100 nm average size. The lyophilized product is of excellent stability. NOAC can be applied as an infusion shortly after reconstitution with physiological buffers. Alternatively, NOAC can be prepared as a microemulsion and as oral and topical formulations.
In vivo Antitumor Activity:
NOAC exerts strong cytotoxic effects in murine L1210 leukemia and in various xenografted human solid tumors (leukemias, breast, prostate and lung tumors) after intravenous, intraperitoneal and oral application. The excellent antileukemic activity of NOAC after ORAL treatment is shown here:
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In vitro Cytotoxicity:
NOAC is highly cytotoxic on various tumor cell lines (e.g. HL-60, HL-60/ara-C resistant, U937, K562, CCRF-CEM, CCRF-CEM/dCK deficient, KB-3-1, PC-3, DU-145, Daudi) and on freshly biopsized human tumor cells (e.g. ovarian and mammary carcinomas).
Toxicity and Therapeutical Index:
The dose of acute toxicity in healthy mice after one intraperitoneal application is 524 mg NOAC/kg. NOAC has no amphiphilic properties and has no hemolytic toxicity. The therapeutic index is approximately 16, demonstrating the safety of NOAC. The hematological toxicity is mild with moderate myelosuppression and thrombocytopenia.
Preclinical Pharmacokinetics:
Pharmacokinetics of NOAC in healthy mice gave plasma half-lives of t1/2(a) = < 10 min and t1/2(b) = 7 - 10 hours. A relatively high proportion of the drug is found in the liver, however with similar elimination kinetics as in plasma. A high proportion of NOAC is bound to erythrocytes. Liver metabolites are not known, but it is expected that cytochrome P450 enzymes are metabolizing and dealkylating NOAC. The bioavailability of NOAC after oral drug application is 15 - 20%. The drug is taken up in its intact form.
Deaminase Resistance and Interactions with Blood Components:
NOAC is substantially protected from deamination. In vitro deamination of NOAC in human plasma is more than 40 times lower compared to ara-C, the widely used antileukemic agent. After i.v. administration NOAC binds to erythrocyte membranes, plasma proteins and leukocytes. In plasma, NOAC is distributed into HDL and other plasma proteins, into LDL and into VLDL. In vivo, NOAC is transferred at fast rates from the liposomal formulations to blood components.
Cellular Pharmacology:
In tumor cells (e.g. HL-60, K562, U937, L1210) NOAC is distributed to more than 90% to cell membranes. Total uptake of NOAC into tumor cells is generally 5 to 10-fold higher compared to ara-C. The uptake mechanism of NOAC is independent of the nucleoside transport mechanism known for nucleosides. Blocking of this mechanism does not inhibit NOAC uptake and cytotoxicity. High concentrations of deoxycytidine which also block ara-C activity do not inhibit NOAC cytotoxicity. The intracellular half-life of NOAC is more than five times longer than that of ara-C. Formation of phosphorylated metabolites (e.g. ara-C-triphosphate) from NOAC is significantly lower than from ara-C (< 5%). Correspondingly, DNA incorporation of NOAC is also reduced by factors of 50 - 120. NOAC is significantly less S-phase specific than ara-C and it induces apoptotic cell death only at very high concentrations. It was found that NOAC is not a substrate for human deoxycytidine kinase.
Mechanisms of Action:
NOAC is taken up by tumor cells by a nucleoside transporter independent mechanism. Due to its lipophilic properties, NOAC is taken up by passive membrane diffusion and it seems to influence certain membranal transduction mechanisms. The fact that NOAC is highly cytotoxic in kinase deficient and ara-C and other drug resistant cells (e.g. KB cells), allows to assume that other, unknown action mechanisms are responsible for its excellent cytotoxic activity.
From the presently known pharmacological data it can be postulated that NOAC might possess a very high potential to retain its strong cytotoxic activity in solid tumors and in tumor cells with low numbers of nucleoside transporting molecules (e.g. CML, CLL, lymphomas), in leukemias with low kinase activities (ara-C resistant leukemias) and possibly, due to its different cellular uptake and the lipophilic properties, also in multidrug resistant (MDR1) tumors.
Literature References:
(Including data describing the properties of the analog N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC))
Schwendener, R.A., Schott, H., Treatment of L1210 murine Leukemia with Liposome - incorporated N4-hexadecyl-1-beta-D-arabinofuranosylcytosine. Int. J. Cancer 51: 466-469 (1992).
Schott, H., Häussler, M.P., and Schwendener, R.A. Synthese von 4-Alkyl-cytosinnucleosiden und deren zytostatische Wirkung im L1210 Leukämiemodell der Maus. Liebigs Annalen der Chemie, 465-470 (1994).
D.H. Horber, C. Ottiger, H. Schott and R.A. Schwendener. Pharmacokinetic Properties and Interactions with Blood Components of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) incorporated into Liposomes. J. Pharm. Pharmacol., 47: 282-288 (1995).
D.H. Horber, H. Schott and R.A. Schwendener. Cellular Pharmacology of a liposomal Preparation of N4-hexadecyl-1-b-D-arabinofuranosylcytosine, a lipophilic Derivative of 1-beta-D-arabinofuranosylcytosine. Br. J. Cancer, 71: 957-962, 1995.
D.H. Horber, H. Schott and R.A. Schwendener. Cellular Pharmacology of N4-hexadecyl-1-beta-D-arabinofuranosylcytosine (NHAC) in the human leukemic Cell Lines K-562 and U-937. Cancer Chemother. Pharmacol.,36: 483-492, 1995.
D.H. Horber, P. von Ballmoos, H. Schott and R.A. Schwendener. Cell Cycle dependent Cytotoxicity and Induction of Apoptosis by N4-hexadecyl-1-beta-D-arabinofuranosyl-cytosine, a new lipophilic Derivative of 1-beta-D-arabino-furanosylcytosine. Br. J. Cancer, 72: 1067-1073, 1995.
R.A. Schwendener, D.H. Horber, C. Ottiger, K.M. Rentsch, H.H. Fiebig and H. Schott. Monograph: Alkasar-18, 1-(beta-D-arabinofuranosyl)-4-octadecylamino-2(1H)-pyrimidin-one, N4-octadecyl-ara-C, NOAC. Drugs of the Future, 20: 11-15, 1995.
R.A. Schwendener, D.H. Horber, C. Ottiger and H. Schott. Preclinical Properties of N4-hexadecyl- and N4-octadecyl-1-beta-D-arabinofuranosylcytosine in liposomal Preparations. J. Liposome Res., 5: 27-47, 1995.
Rentsch, K.M., Schwendener, R.A., Schott, H., Hänseler, E. A sensitive High-performance liquid chromatographic Method for the Determination of N4-hexadecyl- and N4-octadecyl-1-beta-D-arabinofuranosylcytosine in Plasma and Erythrocytes. J. Chromatogr. 673: 259-266, 1995.
Schott, H. and Schwendener, R.A. Synthesis ans structure-activity studies in vivo of liposomal phospholipid-N4-palmitoyl- and N4hexadecyl-1-beta-D-arabinofuranosylcytosine conjugates. Anti-Cancer Drug Design 11: 451-462, 1996.
Schott, H. and Schwendener, R.A. Synthesis of liposomal phospholipid-(N4-palmitoyl-1-beta-D-arabinofuranosylcytosine)-conjugates and evaluation of their cytostatic activity against L1210 murine leukemia. Liebigs Annalen der Chemie,365-369, 1996.
Schwendener, R.A., Horber, D.H., Odermatt, B., Rentsch, K.M. and Schott, H. Antitumor activity and pharmacological properties of orally administered lipophilic N4-alkyl derivatives of 1-b-D-arabinofuranosylcytosine (ara-C). J. Cancer Res. Clin. Oncol.122: 102-108, 1996.
Schwendener, R.A. and Schott, H. Lipophilic 1-beta-D-arabinofuranosyl cytosine derivatives in liposomal formulations for oral and parenteral antileukemic therapy in the murine L1210 leukemia model. J. Cancer Res. Clin. Oncol.122: 723-726, 1996.
Rentsch, K.M., Schwendener, R.A., Schott, H., Hänseler, E. Pharmacokinetics of N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) in plasma and whole blood after intravenous and oral application in mice. J. Pharm. Pharmacol.,49: 1076-1081, 1997.
Koller-Lucae, S.K.M, Schott, H., Schwendener, R.A. Pharmacokinetic properties in mice and interactions with human blood in vitro of liposomal N4-octadecyl- 1-beta-D-arabinofuranosylcytosine (NOAC), a new anticancer drug. J. Pharmacol. Exptl. Therap.,282: 1572-1580, 1997.
Have a look at this publication about NOAC interactions with human blood
in the Journal of Pharmacology and Experimental Therapeutics
Have also a look at the exclellent review on the clinical pharmacokinetics of cytarabine (ara-C) and cytarabine derivative formulations, including our liposomal preparations of the various heterodinucleoside dimers by A. Hamada et al., in Clin. Pharmacokinet. 41: 705-18, (2002).
Koller-Lucae, S.K.M., Suter, M. J.-F-, Rentsch, K.M., Schott, H., Schwendener, R.A. Metabolism of the new liposomal anticancer drug N4-octadecyl-1-beta-D-arabinofuranosylcytosine (NOAC) (NOAC) in mice. Drug Metabolism and Disposition,27: 342-3650, 1999.
Koller-Lucae, S.K.M, Schott, H., Schwendener, R.A. Low density lipoprotein and liposome mediated uptake and cytotoxic effect of N4-octadecyl-1-beta-D-arabinofuranosylcytosine in Daudi lymphoma cells. Br. J. Cancer,80: 1542-1549, 1999.
Horber, D.H., Cattaneo-Pangrazzi, R.M.C., von Ballmoos, P., Schott, H., Ludwig, P.S., Eriksson, S., Fichtner, I., Schwendener, R.A. Cytotoxicity, cell cycle perturbations and apoptosis in human tumor cells by lipophilic N4-alkyl- 1-beta-D-arabinofuranosylcytosine derivatives and the new heteronucleoside phosphate dimer arabinocytidylyl-(5'-5')-N4-octadecyl-1-beta-D-ara-C. J. Cancer Res. Clin. Oncol. 126: 311-319, 2000.
Cattaneo-Pangrazzi, R.M.C., Schott, H., Wunderli-Allenspach, H., Derighetti, M.I., and Schwendener, R.A. The novel heterodinucleoside dimer 5-FdU-NOAC is a potent cytotoxic drug and a p53-independent inducer of apoptosis in the androgen-independent human prostate cancer cell lines PC-3 and DU-145. The Prostate 45: 8-18, 2000.
Schwendener, R.A., Feil, K., Depenbrock, H., Schott, H., Hanauske, A.-R. In vitro activity of liposomal N4-octadecyl-1-b-D-arabinofuranosyl-cytosine (NOAC), a new lipophilic derivative of 1-b-D-arabinofuranocylcytosine on biopsized clonogenic human tumour cells and haematopoietic precursor cells. Invest. New Drugs 19: 203-210, 2001.
Marty, C., Ballmer-Hofer, K., Neri, D., Klemenz, R., Schott, H., Schwendener, R.A. Cytotoxic targeting of F9 teratocarcinoma tumours with anti-ED-B fibronectin scFv antibody modified liposomes. Br. J. Cancer 87: 106-112, 2002.
Take also a look at the MEDLINE Publication abstracts (R.A. Schwendener)
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