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Home , Cidofovir

(CANCER RESEARCH 58. 384-388. Febmary I. 1998]

Advances in Brief

The Antiviral Agent Cidofovir [(S)-l-(3-Hydroxy-2-phosphonyl-methoxypropyl) ] Has Pronounced Activity against Nasopharyngeal Carcinoma Grown in Nude Mice1

Johan Neyts,2 Robert Sadler,2 Erik De Clercq, Nancy Raab-Traub, and Joseph S. Pagano3

Lineberger Comprehensive Cancer Center. University of North Carolina, Chapel Hill, North Carolina 27599-7295 ¡J.N., R. S., N, R-T., J. S. P.], and The Rega Institute for Medical Research. Kittholieke Universiteit Leuven, 3000 Leuven, Belgium [J. N., E. D. C.I

Abstract oral HLP,4 which is characterized by abundant EBV replication (6). The major side effect of cidofovir is nephrotoxicity. However, com The effect of the antiviral agent (S)-l-(3-hydroxy-2-phosphonylme- bined use with reverses this adverse effect without affect thoxypropyl) cytosine (cidofovir) on the EBV-associated tumor nasopha ing the antiviral potency of the compound (4). Side effects have not ryngeal carcinoma (NPC) was evaluated in NPC xenografts in athymic been observed on topical application of cidofovir (2). mice. Intratumoral injection arrested tumor growth within 1 week, and by 4 weeks, tumors regressed to 8-75% (39 ±33%) of the original size, In addition, cidofovir produces complete regression of Shope pap- illoma virus-induced lesions in rabbits. Subsequently, a similar dra whereas control tumors injected with PBS grew to 282 ±25% of the original size. slowed but did not arrest or cause regression of matic effect of cidofovir was observed in several patients with severe tumor growth. A striking antitumor effect was also produced by systemic recurrent caused by HPV (7). Cidofovir also administration; at 4 weeks, tumors were 79 ±49% of the original size, proved highly effective in the topical treatment of anogenital HPV compared with 635 ±91% for the controls. Widespread apoptosis was infections in AIDS patients with severe, relapsing penile, perigenital, detected after treatment for 2-6 days in C15 as well as two other NPC intra-anal, or cervical and vulvar condylomata associated with xenografts, C17 and CIS; the latter NPCs have mutations in thep53 gene. HPV-16 (8). More extensive clinical trials are in progress to determine These data indicate that cidofovir induces rapid cell death through apop the safety and efficacy of cidofovir against HPV-associated lesions. tosis in EBV-transformed epithelial cells. NPC, which is universally associated with EBV, is endemic in Chinese in Southeast Asia. In southern China, NPC may account for Introduction 20% of all cancers (9, 10). An age-adjusted incidence of 26 cases per In recent years, the potent and selective anti-DNA virus activity of 100,000 has been reported among males in Hong Kong. Although cidofovir has been discovered and characterized. Cidofovir belongs to resection of the tumor, together with radiation therapy and/or chem a new class of antiviral molecules, the acyclic nucleoside otherapy (cisplatinum and 5-FU), has proven to be effective, relapse analogues. These molecules are active in vitro and in vivo against a and metastasis occur frequently (11, 12). broad range of DNA viruses including herpesviruses, poxviruses, Because NPC, like HPV papillomatosis, is a tumor of epithelial hepadnaviruses, polyomavirus, papillomaviruses, and adenoviruses origin induced by an oncogenic DNA virus, EBV, it was thought that (1). This class of molecules is characterized by a stable phosphonate NPC might respond to the compound. However, in contrast to HLP, linkage between the acyclic nucleoside and the phosphate moiety. As in which there is active replication of EBV, in NPC, EBV infection is a consequence, and in contrast to antiviral drugs such as acyclovir, mainly latent, and the episomal DNA is replicated by a host DNA , and ganciclovir, cidofovir bypasses the first phosphoryl- polymerase (9). Importantly, in both HPV papillomatosis and NPC, ation step by herpesvirus-encoded kinases. On further phosphoryla- the viral episomal forms are both transcribed and replicated by host tion by cellular kinases, the diphosphorylated metabolite selectively polymerases. In this study, cidofovir is shown to have potent activity inhibits the viral DNA polymerization process. Hence, the compound against NPCs that were grown in athymic mice. has potent activity against thymidine kinase-deficient herpesvirus Materials and Methods strains and strains that are deficient in their ability to phosphorylate ganciclovir. Cidofovir has shown promise in clinical Nasopharyngeal Tumors. NPC C15 was established from the primary trials for herpetic infections (2) as well as ocular adenovirus infections nasopharyngeal tumor of a 13-year-old girl; NPC C17 and NPC CIS were (3) and has recently been approved for the i.v. treatment of cytomeg established after radiation and chemotherapy from recurrent cutaneous and alovirus retinitis in patients with AIDS (4). Cidofovir is a potent cervical lymph node métastases,respectively (13). The tumors were propa gated by s.c. passage in athymic nude mice. Tumors (1-2 cnr1) were dissected inhibitor of the replication of EBV in cell culture (5). Inhibition of and trimmed into 2-mm3 pieces. After a brief rinsing in PBS, one-third or EBV replication was confirmed by the recent finding that a single i.v. one-fourth of each tumor was mixed with Matrigel and transplanted s.c. in the administration of 5 mg/kg cidofovir produced complete regression of mice. Tumors appeared in about 70% of the animals 7-8 weeks posttransplan- tation. Received 10/2/97; accepted 12/29/97. Treatment and Evaluation. For intratumoral treatment, tumors between The costs of publication of this article were defrayed in part by the payment of page 0.5 and 1.5 cm3 were injected with 100 /xl of a 1.5% solution of cidofovir charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. (, Foster City, CA) in PBS that was neutralized to pH 7.4 and ' Supported by National Cancer Institute Grants CAI9014 (to J. S. P. and N. R-T.) and sterilized through filtration (Millex-GS, 0.22 JIM: Millipore). Control animals CA32979 (to N. R-T.). J. N. is a postdoctoral research Fellow from the Flemish Fonds received PBS only. For systemic treatment, animals were injected s.c. in the voor Wetenschappe-lijk Onderzoek and is supported by the D. Collen Research Founda tion/Belgian-American Educational Foundation. 2 R. S. and J. N. contributed equally to this work. 4 The abbreviations used are: HLP. hairy leukoplakia; HPV. human papillomavirus; ' To whom requests for reprints should be addressed, at the Lineberger Comprehensive c-HPMPC, cyclic (S)-l-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine; NPC, naso Cancer Center. University of North Carolina, Campus Box 7295. Chapel Hill. NC pharyngeal carcinoma; 5-FU, 5-fluorouracil; TÚNEL, terminal deoxynucleotidyl trans- 27599-7295. ferase-mediated dUTP nick-end labeling; EBER, EBV-encoded RNA. 384

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1998 American Association for Cancer Research. CIDOFOVIR AND NPC neck with 100 mg/kg/day cidofovir 5 days a week or with PBS only. Treatment tively, after start of treatment), in contrast to the cidofovir-treated was continued as indicated in the figure legends. Ganciclovir was used as a tumors, regression in tumor size was not observed. reference treatment; animals were injected with 150 ju.1of a 1% (75 mg/kg) To determine whether systemic treatment with cidofovir was also neutralized solution. Tumor size was estimated weekly by measuring the effective in reducing the growth of the CIS tumors (Fig. Iß),cido dimensions of the tumors with calipers. fovir (100 mg/kg/day, 5 days a week) was administered s.c. starting Histology, Staining for Apoptosis, and in Situ Hybridization for EBV with tumors that had reached sizes of 0.25-0.65 cm\ Four weeks after EBER RNA. The tumors were dissected at different times after the start of treatment, and portions of the tumors were fixed in 10% buffered formalde the start of treatment, most of the tumors had not increased in size but hyde and embedded. Paraffin sections were stained with H&E. In siiu hybrid had regressed (mean tumor size, 79 ±69% of the size at the start of ization for EBER RNA was performed as described previously (10. 14) using treatment). Control tumors increased in the same time span to volumes a fluorescein-tagged 30-bp oligonucleotide complementary to the EBER1 of 635 ±91% of the initial size. RNA sequence from nucleotides 6697-6726. After deparaffmation, sections To determine the effect of cidofovir on the tumors at early times were digested tor 10 min with 25 fig/ml proteinase K. Prehybridization was performed with a solution containing 20 mM sodium phosphate. Denhardt's after the start of treatment, the tumor masses were dissected and processed for histology, in situ hybridization for EBER RNA, and solution (0.02% Ficoll. 0.02% polyvinylpyrrolidone, and 0.02% BSA) for 30 min at 37°Cfollowed by a 2-h hybridization in the prehybridization solution staining for apoptosis. At the start of treatment in the animals treated containing 50 nmol/ml labeled oligonucleotide at 37°C.Hybridization was with PBS, distinct epithelial tumor masses of typical undifferentiated detected by incubation with rabbit antifluorescein antibody tagged with alka NPC surrounded by mouse stromal tissue were present (Fig. 2A). In line phosphatase. followed by reaction with the substrate, 5-bromo-4-chloro- these tumors, a small number of apoptotic cells were detected (Fig. 3-indolyl phosphate, and the colorimetrie indicator, nitroblue tetrazolium. 2B). As early as 2 days after intratumoral injection with cidofovir, Apoptosis in (he tumor sections was detected by the TÚNEL test according to histological examination revealed loss of cellularity, anuclear cellular the manufacturer's instructions (Boehringer Mannheim). Sections were eval debris, vascular congestion and hemorrhage, and infiltrating cells uated by fluorescence microscopy. (Fig. 2C). Condensed nuclei in H&E-stained sections suggested an increase in apoptotic cells that was confirmed by TÚNEL staining. Results The apoptotic cells were concentrated in the affected area, in contrast In the first set of experiments, 100 ^1 of cidofovir (1.5%; 60 to the small number of apoptotic tumor cells in the unaffected region mg/kg/day) were injected into CIS tumors that had reached sizes of of the tumor (Fig. 2D). This finding was consistent with the macro 0.5-1.5 ran3 (Fig. 1-4).Four to 5 days after the start of treatment, white scopic appearance of white patches on the tumor surface 4-5 days patches appeared on the surface of most of the cidofovir-injected after the start of cidofovir treatment. tumors. Overall, tumor size was reduced to 39 ±33% of the initial On day 6, matched sections revealed almost complete destruction of tumor volume 4 weeks after the initiation of cidofovir treatment. A tumor with large regions of anuclear debris, apoptotic tumor cells, and second NPC xenograft (C17) also regressed to 87% of the initial large numbers of infiltrating lymphocytes, neutrophils, and macro tumor volume after intratumoral treatment with cidofovir (data not phages (Fig. 3, A and D). A remnant of viable tumor cells adjacent to shown). Control C15 tumors that had been injected with PBS at the the capsule still contained detectable EBERs (Fig. 3. ßandE, left) and same time grew to sizes of 282 ±25% of the initial volume. Ganci was TUNEL-negative (Fig. 3, C and F, left). EBER RNAs are abun clovir is another with anti-EBV activity that has dant, nonpolyadenylated small nRNAs that are present in approxi mately IO6 copies per infected cell. These RNAs are not expressed in cytostatic activity in cell culture comparable to or greater than that of cidofovir (15). Although growth of the ganciclovir-treated tumors was HLP and are considered a marker of latently infected. EBV-trans- reduced as compared to the controls (125 ±17, 146 ±11, 154 ±34, formed cells (6). However, the main body of the tumor was massively and 157 ±21% of the initial size at 7, 14, 21, and 28 days, respec apoptotic (Fig. 3, C and F, right) and EBER negative (Fig. 3, ßand

Fig. 1. Treatment of NPC in athymic mice with cidofovir. A, change in tumor volume in animals injected intratumorally with I(K) u.1 of a 1.5% cidofovir solution (D) or PBS (M). Treatment was initiated when the tumors had reached a size of about 0.5-1.5 cm1 and was continued 5 days a week until the end of the experiment. The cidofovir and the PBS groups contained 7 and 6 mice, respectively. B. change in tumor volume in animals injected s.c. with 100 mg/kg/day cidofovir (D: B u = 8) or PBS A. Treatment was started when the tumors reached sizes of 0.25-0.65 cm* and was continued 5 days a week until the end of the experiment.

Day 7 Day 14 Day 21 Day : 385

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Fig. 2. Effects of cidofovir early after inocula tion. Histological sections of the CI5 tumor arc shown hefore the start of treatment (A and B) or 2 days after (he start of intratumoral injection of cidofovir (C and D}. H&E staining. A and C. TÚNEL staining, B and D. Magnification, X200 (A and if) and X50 (C and D}.

E). By 4 weeks, the remaining tumor consisted almost entirely of replication of EBV (5) but does not affect EBV episomal copy number amorphous dead tissue. or the growth of latently infected cells (15). The CIS, C17, and CIS NPCs carrying a mutant p53 gene, C17 and CIS, were also ana tumors have many of the characteristic features of NPC including lyzed (16). Histological examination after intratumoral injection with histology, cell markers, maintenance of a fixed EBV episomal copy cidofovir for 6 days revealed extensive apoptosis (Fig. 4). The un number, expression of type 2 EBV latency antigens, and lack of viral treated animals had viable tumors with few apoptotic cells (Fig. 4, A, replication ( 13). Therefore, the mechanism of the inhibitory effect of B, E, and F). whereas the treated C17 and CIS tumors had a histo cidofovir on growth of NPC must be distinct from its antiviral po- lógica!appearance with massive apoptosis, similar to the CIS tumors lymerase activity, because the CIS as well as C17 and CIS cells, (Fig. 4, C, D, G, and H). which are latently infected, do not express the EBV DNA polymerase. Although HPV is produced in papillomas, whereas NPC represents a Discussion non-virus-producing transformed cell infection state, in both cases the This study was designed to determine whether the antiviral agent viral genomes are replicated as episomes by host DNA polymerase, cidofovir has potential antitumor activity against NPC. In its diphos- and viral genes are expressed by host RNA polymerase. Cidofovir phorylated form, cidofovir inhibits herpesvirus-encoded DNA poly- may possibly affect one of these biochemical processes. merases (17, 18). The compound is a potent inhibitor of the cytolytic In the present study, there was a dramatic decrease in the size of

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Fig. 3. Decreased EBV EBER expression during apoptosis induced by cidofovir. Matched sections of CIS tumor sampled on day 6 of trealment were stained with H&E (A and D). hybridized in situ for EBER IB and £),or stained with the TÚNEL lest (C and F}. Magnification, X 100 (A. B, and C) and X400 (D, E, and F). 386

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Fig. 4. Induction of apoptosis in NPC without p53 mutations. Matched sections of CI7 (A~D) and CIS (E-H) tumors, either untreated (A. B. E, and /•')ortreated lor 6 days (C, D. G. and H}. were stained with H&E (A. C. E, and G) and with the TÚNEL test (B. D. F. and //). Magnification. X200.

established NPCs in mice when cidofovir was injected intratumorully. As early as 2 days after the start of treatment, there was a large Systemic treatment with cidofovir also produced a striking tumoristatic increase in the number of apoptotic tumor cells. Drug-induced apop effect with substantial tumor regression in half the animals. The obser tosis is a mechanism by which many antitumor agents elicit antitumor vation that not all tumors regressed may reflect the lower concentration of activity ( 19). Cidofovir is a compound with low m vitra cytotoxic and cidofovir in the tumors in animals receiving the compound s.c. Ganci- cytostatic action (20) (e.g., more than l().(HM)-foldless cytoslatic than clovir. which has greater cytostatic activity than cidofovir in cell culture, or daunorubicin). Cidofovir also induces apoptosis in did not cause tumor regression on intratumoral injection; tumors contin HPV-containing cell lines, paralleling the pronounced antitumor ac ued to grow, although they grew more slowly. tivity of cidofovir against HPV papillomas. Although NPC cannot be 387

Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 1998 American Association for Cancer Research. CIDOFOVIR AND NPC cultured in vitro for similar studies, the tumor cells seemed to be Treatment of adenoviral conjunctivitis with topical cidofovir. Cornea. 15: 546. 1996. Lalezari, J. P.. Stagg. R. J.. Kuppermann. B. D.. Holland. G. R.. Kramer. F.. Ivés, specifically targeted, because the surrounding tissues were not af D. V.. Youle. M.. Robinson. M. R.. Drew. W. L., and Jaffe. H. R. Intravenous fected by the compound. cidofovir for peripheral cytomegalovirus retinitis in patients with AIDS: a random Nucleoside analogues with antitumor activity such as arabinocy- ized, controlled trial. Ann. Inlern. Med.. 126: 257-263. 1997. tosine, gemcitabine. and 5-FU as well as other agents, e.g., daunoru- Lin. J. C.. De Clercq. E.. and Pagano. J. S. Inhibitory effects of acyclic nucleoside phosphonate analogs, including (S)-l-(3 hydroxyphosphonylmethoxypropyl) cytosine, on bicin, cisplatinum. and etoposide. induce apoptosis. The signaling Epstein-Barr virus replication. Antimicroh. Agents Chemother.. 35: 2440-2443, 1991. pathways that initiate drug-induced apoptosis remain largely unknown 6- Gilligan. K.. Rajadurai. P.. Resnick. L.. and Raab-Traub. N. Epstein-Barr virus small RNAs are not expressed in permissively infected cells in AIDS-associated leukopla- but are distinct from those associated with apoptosis induced by the kia. Proc. Nati. Acad. Sci. USA. 87: 8790-8794. 1990. FAS receptor (21). In addition, the induction of apoptosis by cidofovir 7. Van Culsem, E.. Snoeck, R.. Van Ransl, M., Fiten. P.. Opdenakker. G.. Geboes, K.. must not be dependent on the p53 gene, because the C17 and C18 Janssens. J.. Rutgeers, P., Vantrappen, G., and De Clercq. E. Successful treatment of a squamous papilloma of the hypopharynx-oesophagus by local injections of (S)-I-(3- tumors have deletions in the p53 gene, whereas CIS has wild-type hydroxy-2-phosphonylmethoxypropyl) cytosine. J. Med. Virol.. 45: 230-235, 1995. p53, as do most NPCs (16). Gemcitabine monophosphate induces 8. Snoeck. R.. Van Ransl. M., Andrei. G.. De Clercq. E.. De Wit. S.. Poncin. M.. and apoptosis due to incorporation into cellular DNA (22). Interestingly, Clumeck. N. Treatment of anogenital papillomavirus infections with an acyclic nucleoside phosphonate analogue. N. Engl. J. Med., 333: 943-944. 1995. cidofovir also has the potential to incorporate into DNA (23). It is also 9 Raab-Traub. N. Epstein-Barr virus and nasopharyngeal carcinoma. Semin. Cancer possible that disruption of the cell cycle, shown for 5-FU and meth- Biol., 3: 297-307, 1992. Pathmanathan, R., Prasad. U.. Gangatharan, C.. Sadler. R.. Flynn, K.. and Raab- otrexate (24), may be a trigger for apoptosis. Traub. N. Undifferentiated. nonkeratinizing. and squamous cell carcinoma of the Tumor viruses encode proteins that inhibit apoptosis in infected nasopharynx. Am. J. Patirai.. ¡46: 1355-1367. 1995. cells. The HPV E6 gene promotes p53 degradation, and EBV also n. Teo. P.. Leung, T. W.. Chan. A. T., Yu. P., Lee, W. Y., Leung, S. F., Kwan, W. H.. and Johnson. P. A retrospective study of the use of cisplatinum-5-fluorouracil expresses proteins that inhibit apoptosis. In permissive infection, EBV neoadjuvant chemotherapy in cervical-node-positive nasopharyngeal carcinoma encodes a gene, BHRFl. that is homologous to bcl2 and inhibits (NPCl. Eur. J. Cancer. Part B. Oral Oncol.. 31B: 373-379, 1995. apoptosis. In latent infection, LMP1 specifically inhibits p53-medi- '2. Dugan. M.. Choy. D.. Ngai. A.. Sham. J.. Choi. P., Shiu. W., Leung, T.. Teo, P., Prasad, U., Lee, S., Villalon. A.. Tan. B.. Chen. K. Y., Hsu. M. M.. Vootitrux. V.. Dy. ated apoptosis though induction of expression of the bcl2 and A20 E.. Hoffman. A.. Reisman. A., and Neal. J. Multicenter Phase II trial of mitoxantrone genes (25). The absence of detectable EBER RNAs in the affected in patients with advanced nasopharyngeal carcinoma in Southeast Asia: an Asian- tissue raises the possibility that there is inhibition of viral expression, Oceanian Clinical Oncology Association Group Study. J. Clin. Oncol.. //: 70-76, 1993. which might enhance susceptibility to apoptosis either from inducers ^ Busson. P.. Ganem. G.. Flores. P.. Mugneret. F.. Clausse. B., Caillou. B.. Brahan. K.. such as tumor necrosis factor or possibly through the DNA-damaging Wakasugi. H.. Lipinski. M.. and Tursz. T. Establishment and characterization of three effects of cidofovir incorporation. transplantable EBV-containing nasopharyngeal carcinomas. Int. J. Cancer. 42: 599- 606. 1988. In the clinical setting, intralesional treatment of HPV papillomas |4 Chang. K. L.. Chen. Y. Y.. Shibata. D.. and Weiss. L. M. Detection of an in situ with cidofovir has been well tolerated. Doses used were 1.25 mg/kg or hybridization methodology for detection of Epstein-Barr virus RNA in paraffin- 3-12 ml of a 2.5% cidofovir solution (7). Side effects were not embedded tissues, with a survey of normal and neoplastic tissue. Diagn. Mol. Pathol.. /: 246-255. 1992. observed with these doses, and most papillomas disappeared com- 15 Pagano. J. S. Epstein-Barr virus. In: D. J. Jeffries and E. De Clercq (eds.l. Antiviral pletely. Thus, intratumoral treatment of NPC with cidofovir may be Chemotherapy, pp. 155-195. New York: John Wiley & Sons Ltd., 1995. expected to be well tolerated. When combined with probenecid, lf> Effert. P.. Abdel-Hamid. M.. McCoy. R.. Flynn. K.. Busson. P.. Zhang. Q., Tursz. T., Liu. E.. and Raab-Traub. N. Alterations of the p53 gene in nasopharyngeal carcinoma. toleration of systemic treatment with cidofovir is improved (26). J. Virol.. 66: 3768-3775, 1992. Moreover, the cyclic ester derivative of cidofovir. c-HPMPC, is 17. Neyts. J.. and De Clercq. E. Mechanism of action of acyclic nucleoside 13-fold less nephrotoxic than the parent compound in animal models; against herpes virus replication. Biochem. Pharmacol.. 47: 39-41. 1994. 1X. Xiong, X.. Smith. J. L.. Kim. C.. Huang. E.. and Chen. M. S. Kinetic analysis of the however, c-HPMPC seems to be hepatotoxic (27). Intracellularly, interaction of cidofovir diphosphate with human cytomegalovirus DNA polymerase. c-HPMPC is readily converted to cidofovir by cyclic CMP phospho- Biochem. Pharmacol., 51: 1563-1567. 1996. diesterase (28). Because c-HPMPC can be viewed as the intracellular 19. Wang. C. Y.. Mayo. M. W.. and Baldwin. A. S.. Jr. TNF- and cancer therapy-induced apoptosis: potentiation by inhibition of NF-xB. Science (Washington). 274: 784-787. prodrug of cidofovir, it is expected to have anti-NPC activity similar 1996. to that of cidofovir and possibly an improved safety profile. 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Johan Neyts, Robert Sadler, Erik De Clercq, et al.

Cancer Res 1998;58:384-388.

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