Physicochemical Considerations of Tumor Selective Drug Delivery and Activity Confinement with Particular Reference to 1,2-Bis(Sulfonyl)-1- Alkylhydrazines Delivery

Author(s): Philip Penketh*, Hugh Williamson, Krishnamurthy Shyam

Journal Name: Current Drug Delivery

Volume 17 , Issue 5 , 2020


Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Abstract:

Hypoxic tumor cell sub-populations are highly resistant to radiotherapy and their presence frequently causes disease recurrence and death. Here, we described the physicochemical properties required to develop superior tumor-targeted hypoxia-activated modular prodrugs that liberate extremely short-lived bis(sulfonyl)hydrazines (BSHs) as reactive cytotoxins, thereby precisely focusing cytotoxic stress on these radio-resistant hypoxic sub-populations. Therefore, cytotoxic stress will be focused on radiation resistant areas and thus strongly synergizing with radiotherapy.

Keywords: Hypoxic tumor cell, bis(sulfonyl)hydrazines (BSHs), cytotoxic stress, hypoxic sub-populations, radiotherapy, hypoxic sub-populations.

[1]
Dougan, M.; Dranoff, G.; Dougan, S.K. Cancer immunotherapy: beyond checkpoint blockade. Annual Rev. Cancer Biol., 2019, 3, 55-75.
[2]
Santini, A.; Tenore, G.C.; Novellino, E. Nutraceuticals: A paradigm of proactive medicine. Eur. J. Pharm. Sci., 2017, 96, 53-61.
[http://dx.doi.org/10.1016/j.ejps.2016.09.003] [PMID: 27613382]
[3]
Daliu, P.; Santini, A.; Novellino, E. From pharmaceuticals to nutraceuticals: bridging disease prevention and management. Expert Rev. Clin. Pharmacol., 2019, 12(1), 1-7.
[http://dx.doi.org/10.1080/17512433.2019.1552135] [PMID: 30484336]
[4]
Fang, J.; Nakamura, H.; Maeda, H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv. Drug Deliv. Rev., 2011, 63(3), 136-151.
[http://dx.doi.org/10.1016/j.addr.2010.04.009] [PMID: 20441782]
[5]
Awwad, H.K.; Naggar, M.; Mocktar, N.; Barsoum, M. Intercapillary distance measurement as an indicator of hypoxia in carcinoma of the cervix uteri. Int. J. Radiat. Oncol. Biol. Phys., 1986, 12(8), 1329-1333.
[http://dx.doi.org/10.1016/0360-3016(86)90165-3] [PMID: 3759554]
[6]
Leach, R.M.; Treacher, D.F. Oxygen transport-2. Tissue hypoxia. BMJ, 1998, 317(7169), 1370-1373.
[http://dx.doi.org/10.1136/bmj.317.7169.1370] [PMID: 9812940]
[7]
Tannock, I.F. Oxygen diffusion and the distribution of cellular radiosensitivity in tumours. Br. J. Radiol., 1972, 45(535), 515-524.
[http://dx.doi.org/10.1259/0007-1285-45-535-515] [PMID: 5067983]
[8]
Wilson, W.R.; Hay, M.P. Targeting hypoxia in cancer therapy. Nat. Rev. Cancer, 2011, 11(6), 393-410.
[http://dx.doi.org/10.1038/nrc3064] [PMID: 21606941]
[9]
Braun, R.D.; Lanzen, J.L.; Snyder, S.A.; Dewhirst, M.W. Comparison of tumor and normal tissue oxygen tension measurements using OxyLite or microelectrodes in rodents; AJP - Heart, 2001, pp. 2533-2544.
[10]
Brizel, D.M.; Sibley, G.S.; Prosnitz, L.R.; Scher, R.L.; Dewhirst, M.W. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int. J. Radiat. Oncol. Biol. Phys., 1997, 38(2), 285-289.
[http://dx.doi.org/10.1016/S0360-3016(97)00101-6] [PMID: 9226314]
[11]
Penketh, P.G.; Shyam, K.; Baumann, R.P.; Ratner, E.S.; Sartorelli, A.C. A simple and inexpensive method to control oxygen concentrations within physiological and neoplastic ranges. Anal. Biochem., 2015, 491, 1-3.
[http://dx.doi.org/10.1016/j.ab.2015.08.032] [PMID: 26361820]
[12]
Pruijn, F.B.; Sturman, J.R.; Liyanage, H.D.; Hicks, K.O.; Hay, M.P.; Wilson, W.R. Extravascular transport of drugs in tumor tissue: effect of lipophilicity on diffusion of tirapazamine analogues in multicellular layer cultures. J. Med. Chem., 2005, 48(4), 1079-1087.
[http://dx.doi.org/10.1021/jm049549p] [PMID: 15715475]
[13]
van der Heijden, M.; de Jong, M.C.; Verhagen, C.V.M.; de Roest, R.H.; Sanduleanu, S.; Hoebers, F.; Leemans, C.R.; Brakenhoff, R.H.; Vens, C.; Verheij, M.; van den Brekel, M.W.M. Acute hypoxia profile is a stronger prognostic factor than chronic hypoxia in advanced stage head and neck cancer patients. Cancers (Basel), 2019, 11(4), 583-596.
[http://dx.doi.org/10.3390/cancers11040583] [PMID: 31027242]
[14]
Lin, A.J.; Cosby, L.A.; Shansky, C.W.; Sartorelli, A.C. Potential bioreductive alkylating agents. 1. Benzoquinone derivatives. J. Med. Chem., 1972, 15(12), 1247-1252.
[http://dx.doi.org/10.1021/jm00282a011] [PMID: 4635968]
[15]
Sartorelli, A.C. Therapeutic attack of hypoxic cells of solid tumors: presidential address. Cancer Res., 1988, 48(4), 775-778.
[PMID: 3123053]
[16]
Lin, A.J.; Cosby, L.A.; Sartorelli, A.C. Potential bioreductive alkylating agents.; Sartorelli, A.C., Ed.; American Chemical Society: Washington, D.C. Cancer Chemother, 1976, pp. 71-86.
[17]
Lin, A.J.; Pardini, R.S.; Cosby, L.A.; Lillis, B.J.; Shansky, C.W.; Sartorelli, A.C. Potential bioreductive alkylating agents. 2. Antitumor effect and biochemical studies of naphthoquinone derivatives. J. Med. Chem., 1973, 16(11), 1268-1271.
[http://dx.doi.org/10.1021/jm00269a010] [PMID: 4147836]
[18]
Le, Q-T.; Denko, N.C.; Giaccia, A.J. Hypoxic gene expression and metastasis. Cancer Metastasis Rev., 2004, 23(3-4), 293-310.
[http://dx.doi.org/10.1023/B:CANC.0000031768.89246.d7] [PMID: 15197330]
[19]
Moulder, J.E.; Rockwell, S. Tumor hypoxia: its impact on cancer therapy. Cancer Metastasis Rev., 1987, 5(4), 313-341.
[http://dx.doi.org/10.1007/BF00055376] [PMID: 3552280]
[20]
Vaupel, P.W.; Frinak, S.; Bicher, H.I. Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res., 1981, 41(5), 2008-2013.
[PMID: 7214369]
[21]
Minchinton, A.I.; Tannock, I.F. Drug penetration in solid tumours. Nat. Rev. Cancer, 2006, 6(8), 583-592.
[http://dx.doi.org/10.1038/nrc1893] [PMID: 16862189]
[22]
Stohrer, M.; Boucher, Y.; Stangassinger, M.; Jain, R.K. Oncotic pressure in solid tumors is elevated. Cancer Res., 2000, 60(15), 4251-4255.
[PMID: 10945638]
[23]
Hicks, K.O.; Pruijn, F.B.; Secomb, T.W.; Hay, M.P.; Hsu, R.; Brown, J.M.; Denny, W.A.; Dewhirst, M.W.; Wilson, W.R. Use of three-dimensional tissue cultures to model extravascular transport and predict in vivo activity of hypoxia-targeted anticancer drugs. J. Natl. Cancer Inst., 2006, 98(16), 1118-1128.
[http://dx.doi.org/10.1093/jnci/djj306] [PMID: 16912264]
[24]
Quintiliani, M. Modification of radiation sensitivity: the oxygen effect. Int. J. Radiat. Oncol. Biol. Phys., 1979, 5(7), 1069-1076.
[http://dx.doi.org/10.1016/0360-3016(79)90621-7] [PMID: 389899]
[25]
Conley, S.J.; Gheordunescu, E.; Kakarala, P.; Newman, B.; Korkaya, H.; Heath, A.N.; Clouthier, S.G.; Wicha, M.S. Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc. Natl. Acad. Sci. USA, 2012, 109(8), 2784-2789.
[http://dx.doi.org/10.1073/pnas.1018866109] [PMID: 22308314]
[26]
Rasheed, Z.A.; Kowalski, J.; Smith, B.D.; Matsui, W. Concise review: Emerging concepts in clinical targeting of cancer stem cells. Stem Cells, 2011, 29(6), 883-887.
[http://dx.doi.org/10.1002/stem.648] [PMID: 21509907]
[27]
Koh, W.J.; Rasey, J.S.; Evans, M.L.; Grierson, J.R.; Lewellen, T.K.; Graham, M.M.; Krohn, K.A.; Griffin, T.W. Imaging of hypoxia in human tumors with [F-18]fluoromisonidazole. Int. J. Radiat. Oncol. Biol. Phys., 1992, 22(1), 199-212.
[http://dx.doi.org/10.1016/0360-3016(92)91001-4] [PMID: 1727119]
[28]
Brown, J.M. Imaging tumor sensitivity to a bioreductive prodrug: two for the price of one! Clin. Cancer Res., 2012, 18(6), 1487-1489.
[http://dx.doi.org/10.1158/1078-0432.CCR-11-3267] [PMID: 22317761]
[29]
Riesterer, O.; Honer, M.; Jochum, W.; Oehler, C.; Ametamey, S.; Pruschy, M. Ionizing radiation antagonizes tumor hypoxia induced by antiangiogenic treatment. Clin. Cancer Res., 2006, 12(11 Pt 1), 3518-3524.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2816] [PMID: 16740778]
[30]
Kyle, A.H.; Minchinton, A.I. Measurement of delivery and metabolism of tirapazamine to tumour tissue using the multilayered cell culture model. Cancer Chemother. Pharmacol., 1999, 43(3), 213-220.
[http://dx.doi.org/10.1007/s002800050886] [PMID: 9923551]
[31]
Penketh, P.G.; Shyam, K.; Baumann, R.P.; Ishiguro, K.; Patridge, E.V.; Zhu, R.; Sartorelli, A.C. A strategy for selective O(6)-alkylguanine-DNA alkyltransferase depletion under hypoxic conditions. Chem. Biol. Drug Des., 2012, 80(2), 279-290.
[http://dx.doi.org/10.1111/j.1747-0285.2012.01401.x] [PMID: 22553921]
[32]
Foehrenbacher, A.; Secomb, T.W.; Wilson, W.R.; Hicks, K.O. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling. Front. Oncol., 2013, 3, 314.
[http://dx.doi.org/10.3389/fonc.2013.00314] [PMID: 24409417]
[33]
Shyam, K.; Penketh, P.G.; Baumann, R.P.; Finch, R.A.; Zhu, R.; Zhu, Y.L.; Sartorelli, A.C. Antitumor sulfonylhydrazines: design, structure activity relationships, resistance mechanisms, and strategies for improving therapeutic utility. J. Med. Chem., 2015, 58(9), 3639-3671.
[http://dx.doi.org/10.1021/jm501459c] [PMID: 25612194]
[34]
Penketh, P.G.; Shyam, K.; Sartorelli, A.C. Studies on the mechanism of decomposition and structural factors affecting the aqueous stability of 1,2-bis(sulfonyl)-1-alkylhydrazines. J. Med. Chem., 1994, 37(18), 2912-2917.
[http://dx.doi.org/10.1021/jm00044a012] [PMID: 8071939]
[35]
Webb, B.A.; Chimenti, M.; Jacobson, M.P.; Barber, D.L. Dysregulated pH: a perfect storm for cancer progression. Nat. Rev. Cancer, 2011, 11(9), 671-677.
[http://dx.doi.org/10.1038/nrc3110] [PMID: 21833026]
[36]
Ishiguro, K.; Zhu, Y-L.; Shyam, K.; Penketh, P.G.; Baumann, R.P.; Sartorelli, A.C. Quantitative relationship between guanine O(6)-alkyl lesions produced by Onrigin™ and tumor resistance by O(6)-alkylguanine-DNA alkyltransferase. Biochem. Pharmacol., 2010, 80(9), 1317-1325.
[http://dx.doi.org/10.1016/j.bcp.2010.07.022] [PMID: 20654586]
[37]
Baumann, R.P.; Penketh, P.G.; Ishiguro, K.; Shyam, K.; Zhu, Y.L.; Sartorelli, A.C. Reductive activation of the prodrug 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119) selectively occurs in oxygen-deficient cells and overcomes O(6)-alkylguanine-DNA alkyltransferase mediated KS119 tumor cell resistance. Biochem. Pharmacol., 2010, 79(11), 1553-1561.
[http://dx.doi.org/10.1016/j.bcp.2009.12.004] [PMID: 20005211]
[38]
Ishiguro, K.; Shyam, K.; Penketh, P.G.; Sartorelli, A.C. Development of an O(6)-alkylguanine-DNA alkyltransferase assay based on covalent transfer of the benzyl moiety from [benzene-3H]O(6)-benzylguanine to the protein. Anal. Biochem., 2008, 383(1), 44-51.
[http://dx.doi.org/10.1016/j.ab.2008.08.009] [PMID: 18783719]
[39]
Citron, M.; Decker, R.; Chen, S.; Schneider, S.; Graver, M.; Kleynerman, L.; Kahn, L.B.; White, A.; Schoenhaus, M.; Yarosh, D. O6-methylguanine-DNA methyltransferase in human normal and tumor tissue from brain, lung, and ovary. Cancer Res., 1991, 51(16), 4131-4134.
[PMID: 1868433]
[40]
Christmann, M.; Verbeek, B.; Roos, W.P.; Kaina, B. O(6)-Methylguanine-DNA methyltransferase (MGMT) in normal tissues and tumors: enzyme activity, promoter methylation and immunohistochemistry. Biochim. Biophys. Acta, 2011, 1816(2), 179-190.
[PMID: 21745538]
[41]
Zhu, R.; Liu, M.C.; Luo, M.Z.; Penketh, P.G.; Baumann, R.P.; Shyam, K.; Sartorelli, A.C. 4-nitrobenzyloxycarbonyl derivatives of O(6)-benzylguanine as hypoxia-activated prodrug inhibitors of O(6)-alkylguanine-DNA alkyltransferase (AGT), which produces resistance to agents targeting the O-6 position of DNA guanine. J. Med. Chem., 2011, 54(21), 7720-7728.
[http://dx.doi.org/10.1021/jm201115f] [PMID: 21955333]
[42]
Baumann, R.P.; Seow, H.A.; Shyam, K.; Penketh, P.G.; Sartorelli, A.C. The antineoplastic efficacy of the prodrug Cloretazine is produced by the synergistic interaction of carbamoylating and alkylating products of its activation. Oncol. Res., 2005, 15(6), 313-325.
[http://dx.doi.org/10.3727/096504005776404553] [PMID: 16408696]
[43]
Shyam, K.; Penketh, P.G.; Shapiro, M.; Belcourt, M.F.; Loomis, R.H.; Rockwell, S.; Sartorelli, A.C. Hypoxia-selective nitrobenzyloxycarbonyl derivatives of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazines. J. Med. Chem., 1999, 42(5), 941-946.
[http://dx.doi.org/10.1021/jm9805891] [PMID: 10072691]
[44]
Seow, H.A.; Penketh, P.G.; Shyam, K.; Rockwell, S.; Sartorelli, A.C. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4- nitrophenyl)ethoxy]carbonyl]hydrazine: an anticancer agent targeting hypoxic cells Proc Natl Acad Sc., 2005, 102, 9282-7.
[45]
Penketh, P.G.; Baumann, R.P.; Shyam, K.; Williamson, H.S.; Ishiguro, K.; Zhu, R.; Eriksson, E.S.; Eriksson, L.A.; Sartorelli, A.C. 1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[[1-(4-nitrophenyl)ethoxy]carbonyl]hydrazine (KS119): a cytotoxic prodrug with two stable conformations differing in biological and physical properties. Chem. Biol. Drug Des., 2011, 78(4), 513-526.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01193.x] [PMID: 21777394]
[46]
Zhu, R.; Seow, H.A.; Baumann, R.P.; Ishiguro, K.; Penketh, P.G.; Shyam, K.; Sartorelli, A.C. Design of a hypoxia-activated prodrug inhibitor of O6-alkylguanine-DNA alkyltransferase. Bioorg. Med. Chem. Lett., 2012, 22(19), 6242-6247.
[http://dx.doi.org/10.1016/j.bmcl.2012.08.008] [PMID: 22932317]
[47]
Grunbein, W.; Fojtik, A.; Henglein, A. Pulsradiolytische Bestimmung der Absorptions-spektren und Dissoziationskonstanten kurzlebiger halbreduzierter aromatischer Nitroverbindungen. Z. Naturforsch. B, 1969, 24b, 1336-1338.
[http://dx.doi.org/10.1515/znb-1969-1024]
[48]
Einstein, A. On the motion of small particles suspended in liquids at rest required by the molecular-kinetic theory of heat. Ann. Phys., 1905, 17, 549-560.
[http://dx.doi.org/10.1002/andp.19053220806]
[49]
Wardman, P. Reduction potentials of one-electron couples involving free radicals in aqueous solutions. J. Phys. Chem. Data, 1989, 18, 1637-1754.
[http://dx.doi.org/10.1063/1.555843]
[50]
Wardman, P. The importance of radiation chemistry to radiation and free radical biology (The 2008 Silvanus Thompson Memorial Lecture). Br. J. Radiol., 2009, 82(974), 89-104.
[http://dx.doi.org/10.1259/bjr/60186130] [PMID: 19168690]
[51]
Wardman, P. Some reactions and properties of nitro radical-anions important in biology and medicine. Environ. Health Perspect., 1985, 64, 309-320.
[http://dx.doi.org/10.1289/ehp.8564309] [PMID: 3830700]
[52]
Rajapakse, A.; Linder, C.; Morrison, R.D.; Sarkar, U.; Leigh, N.D.; Barnes, C.L.; Daniels, J.S.; Gates, K.S. Enzymatic conversion of 6-nitroquinoline to the fluorophore 6-aminoquinoline selectively under hypoxic conditions. Chem. Res. Toxicol., 2013, 26(4), 555-563.
[http://dx.doi.org/10.1021/tx300483z] [PMID: 23488987]
[53]
Kim, E.Y.; Liu, Y.; Akintujoye, O.M.; Shyam, K.; Grove, T.A.; Sartorelli, A.C.; Rockwell, S. Preliminary studies with a new hypoxia-selective cytotoxin, KS119W, in vitro and in vivo. Radiat. Res., 2012, 178(3), 126-137.
[http://dx.doi.org/10.1667/RR2934.1] [PMID: 22862779]
[54]
Stanford, A.L. Foundations of biophysics.Elsevier, Academic New York USA; , 1975, p. 404.
[55]
Lancaster, J.R., Jr Simulation of the diffusion and reaction of endogenously produced nitric oxide. Proc. Natl. Acad. Sci. USA, 1994, 91(17), 8137-8141.
[http://dx.doi.org/10.1073/pnas.91.17.8137] [PMID: 8058769]
[56]
Hobbie, R.K. Intermediate physics for medicine and biology; Wiley Press, 1978, p. 505.
[57]
Crooks, J.E. Measurement of diffusion coefficients. J. Chem. Educ., 1989, 66, 614-615.
[http://dx.doi.org/10.1021/ed066p614]
[58]
Kimura, H.; Braun, R.D.; Ong, E.T.; Hsu, R.; Secomb, T.W.; Papahadjopoulos, D.; Hong, K.; Dewhirst, M.W. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res., 1996, 56(23), 5522-5528.
[PMID: 8968110]
[59]
Shyam, K.; Penketh, P.G.; Loomis, R.H.; Sartorelli, A.C. Thiolysable prodrugs of 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine with antineoplastic activity. Eur. J. Med. Chem., 1998, 33, 609-615.
[http://dx.doi.org/10.1016/S0223-5234(98)80019-6]
[60]
Rasouli-Nia, A.; Sibghat-Ullah, ; Mirzayans, R.; Paterson, M.C.; Day, R.S., III On the quantitative relationship between O6-methylguanine residues in genomic DNA and production of sister-chromatid exchanges, mutations and lethal events in a Mer- human tumor cell line. Mutat. Res., 1994, 314(2), 99-113.
[http://dx.doi.org/10.1016/0921-8777(94)90074-4] [PMID: 7510369]
[61]
Penketh, P.G.; Baumann, R.P.; Ishiguro, K.; Shyam, K.; Seow, H.A.; Sartorelli, A.C. Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating species. Leuk. Res., 2008, 32(10), 1546-1553.
[http://dx.doi.org/10.1016/j.leukres.2008.03.005] [PMID: 18479747]
[62]
Zhu, R.; Baumann, R.P.; Patridge, E.; Penketh, P.G.; Shyam, K.; Ishiguro, K.; Sartorelli, A.C. Chloroethylating and methylating dual function antineoplastic agents display superior cytotoxicity against repair proficient tumor cells. Bioorg. Med. Chem. Lett., 2013, 23(6), 1853-1859.
[http://dx.doi.org/10.1016/j.bmcl.2013.01.016] [PMID: 23395657]
[63]
Penketh, P.G.; Finch, R.A.; Sauro, R.; Baumann, R.P.; Ratner, E.S.; Shyam, K. pH-dependent general base catalyzed activation rather than isocyanate liberation may explain the superior anticancer efficacy of laromustine compared to related 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)hydrazine prodrugs. Chem. Biol. Drug Des., 2018, 91(1), 62-74.
[http://dx.doi.org/10.1111/cbdd.13057] [PMID: 28636806]


open access plus

Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 5
Year: 2020
Page: [362 - 374]
Pages: 13
DOI: 10.2174/1567201817666200427215044

Article Metrics

PDF: 31
HTML: 4
EPUB: 2
PRC: 2