Safety of Boron Neutron Capture Therapy with Borofalan(10B) and Its Efficacy on Recurrent Head and Neck Cancer: Real-World Outcomes from Nationwide Post-Marketing Surveillance.

BACKGROUND: This study was conducted to evaluate the real-world safety and efficacy of boron neutron capture therapy (BNCT) with borofalan(10B) in Japanese patients with locally advanced or locally recurrent head and neck cancer (LA/LR-HNC). METHODS: This prospective, multicenter observational study was initiated in Japan in May 2020 and enrolled all patients who received borofalan(10B) as directed by regulatory authorities. Patient enrollment continued until at least 150 patients were enrolled, and adverse events attributable to drugs, treatment devices, and BNCT were evaluated. The patients with LA/LR-HNC were systematically evaluated to determine efficacy. RESULTS: The 162 patients enrolled included 144 patients with squamous cell carcinoma of the head and neck (SCCHN), 17 patients with non-SCCHN (NSCCHN), and one patient with glioblastoma. Treatment-related adverse events (TRAEs) were hyperamylasemia (84.0%), stomatitis (51.2%), sialoadenitis (50.6%), and alopecia (49.4%) as acute TRAEs, and dysphagia (4.5%), thirst (2.6%), and skin disorder (1.9%) as more common late TRAEs. In patients with LA/LR-HNC, the overall response rate (ORR) was 72.3%, with a complete response (CR) in 63 (46.0%) of 137 patients with SCCHN. Among 17 NSCCHN patients, the ORR was 64.7%, with eight cases (47.1%) of CR. One- and two-year OS rates in patients with recurrent SCCHN were 78.8% and 60.7%, respectively. CONCLUSIONS: This post-marketing surveillance confirmed the safety and efficacy of BNCT with borofalan(10B) in patients with LA/LR-HNC in a real-world setting.

Pharmacokinetic Study of 14C-Radiolabeled p-Boronophenylalanine (BPA) in Sorbitol Solution and the Treatment Outcome of BPA-Based Boron Neutron Capture Therapy on a Tumor-Bearing Mouse Model.

BACKGROUND AND OBJECTIVE: Boron neutron capture therapy (BNCT) is a binary cancer treatment that combines boron administration and neutron irradiation. The tumor cells take up the boron compound and the subsequent neutron irradiation results in a nuclear fission reaction caused by the neutron capture reaction of the boron nuclei. This produces highly cytocidal heavy particles, leading to the destruction of tumor cells. p-boronophenylalanine (BPA) is widely used in BNCT but is insoluble in water and requires reducing sugar or sugar alcohol as a dissolvent to create an aqueous solution for administration. The purpose of this study was to investigate the pharmacokinetics of 14C-radiolabeled BPA using sorbitol as a dissolvent, which has not been reported before, and confirm whether neutron irradiation with a sorbitol solution of BPA can produce an antitumor effect of BNCT. MATERIALS AND METHODS: In this study, we evaluated the sugar alcohol, sorbitol, as a novel dissolution aid and examined the consequent stability of the BPA for long-term storage. U-87 MG and SAS tumor cell lines were used for in vitro and in vivo experiments. We examined the pharmacokinetics of 14C-radiolabeled BPA in sorbitol solution, administered either intravenously or subcutaneously to a mouse tumor model. Neutron irradiation was performed in conjunction with the administration of BPA in sorbitol solution using the same tumor cell lines both in vitro and in vivo. RESULTS: We found that BPA in sorbitol solution maintains stability for longer than in fructose solution, and can therefore be stored for a longer period. Pharmacokinetic studies with 14C-radiolabeled BPA confirmed that the sorbitol solution of BPA distributed through tumors in much the same way as BPA in fructose. Neutron irradiation was found to produce dose-dependent antitumor effects, both in vitro and in vivo, after the administration of BPA in sorbitol solution. CONCLUSION: In this report, we demonstrate the efficacy of BPA in sorbitol solution as the boron source in BNCT.

Anti-Influenza A Virus Activity of Rhamnan Sulfate from Green Algae Monostroma nitidum in Mice with Normal and Compromised Immunity.

Influenza viruses cause a significant public health burden each year despite the availability of anti-influenza drugs and vaccines. Therefore, new anti-influenza virus agents are needed. Rhamnan sulfate (RS) is a sulfated polysaccharide derived from the green alga Monostroma nitidum. Here, we aimed to demonstrate the antiviral activity of RS, especially against influenza A virus (IFV) infection, in vitro and in vivo. RS showed inhibitory effects on viral proliferation of enveloped viruses in vitro. Evaluation of the anti-IFV activity of RS in vitro showed that it inhibited both virus adsorption and entry steps. The oral administration of RS in IFV-infected immunocompetent and immunocompromised mice suppressed viral proliferation in both mouse types. The oral administration of RS also had stimulatory effects on neutralizing antibody production. Fluorescent analysis showed that RS colocalized with M cells in Peyer's patches, suggesting that RS bound to the M cells and may be incorporated into the Peyer's patches, which are essential to intestinal immunity. In summary, RS inhibits influenza virus infection and promotes antibody production, suggesting that RS is a potential candidate for the treatment of influenza virus infections.

In vitro and in vivo anti-herpes simplex virus activity of monogalactosyl diacylglyceride from Coccomyxa sp. KJ (IPOD FERM BP-22254), a green microalga.

A monogalactosyl diacylglyceride (MGDG) was isolated as an antiviral component from Coccomyxa sp. KJ (IPOD FERM BP-22254) via bioassay-guided fractionation. α-Linolenic acid (C18:3) and 7,10,13-hexadecatrienoic acid (C16:3) accounted for approximately 72% and 23%, respectively, of the MGDG total fatty acids of the MGDG. The MGDG showed virucidal activity against herpes simplex virus type 2 (HSV-2), a pathogen that causes genital herpes. Physical changes in HSV-2 shape were observed after treatment with MGDG, including a decrease in particle size, and possible damage to the viral envelope, as assessed using electron microscopy. In accordance with the morphological findings, virus particles lost their ability to bind to host cells. HSV-2 treated with high concentrations of MGDG resulted in no pathogenicity in an animal model, indicating that MGDG exhibits irreversible virucidal activity against HSV-2 particles. In the animal model of HSV-2-induced genital herpes, intravaginally administered MGDG exerted a prophylactic effect by suppressing viral yields in the genital cavity and formation of herpetic lesions, resulting in a higher survival rate in treated mice than control mice administered solvent. Thus, MGDG offers a novel prophylactic option against HSV infections.

Lectin microarray analysis of isolated polysaccharides from Sasa veitchii.

We report lectin microarray profile of the polysaccharide fraction derived from Sasa veitchii leaf that exhibits anti-influenza activity. This fraction showed higher reactivities with lectins known as binders to oligo-mannose, fucose, or galactose. Our findings along with previously reported monosaccharide components suggest that the polysaccharide can be cross-reactive with cell surface receptors involved in immune system, thereby exerting anti-influenza activity.

In vitro and in vivo antiherpetic effects of (1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol.

In this study, we demonstrated the in vitro and in vivo antiherpetic activities of a stable furan derivative, (1R,2R)-1-(5'-methylful-3'-yl)propane-1,2,3-triol (MFPT), which had originally been isolated from Streptomyces sp. strain FV60. In the present study, we synthesized MFPT from (5-methylfuran-3-yl)methanol in 6 steps for use in the experiments. MFPT showed potent in vitro antiviral activities against two acyclovir (ACV)-sensitive (KOS and HF) strains and an ACV-resistant (A4-3) strain of herpes simplex virus type 1 (HSV-1) and an ACV-sensitive HSV type 2 (HSV-2) UW 268 strain, their selectivity indices ranging from 310 to 530. By intravaginal application of MFPT to mice, the virus yields decreased dose-dependently against the three strains of HSV-1 and HSV-2. When MFPT was applied at a dose of 1.0 mg/day, the lesion scores, as clinical signs manifested by viral infection, were extensively suppressed in HSV-1-infected mice, whereas the lesion scores in HSV-2-infected mice were not markedly decreased. Interestingly, MFPT exerted an inhibitory effect against ACV-resistant HSV-1 in mice to a similar degree as in ACV-sensitive HSV-1-infected mice. Therefore, the compound might have potential for developing a topical antiviral agent that could be also applied to the infections caused by ACV-resistant viruses.

Characterization of a novel mutation in NS1 protein of influenza A virus induced by a chemical substance for the attenuation of pathogenicity.

It is generally accepted that live attenuated influenza vaccine (LAIV) has the potential for use as a vaccination against flu. In this study, we demonstrated the nature of an influenza A virus (IAV) mutant induced by treating the IAV with a stable furan derivative, (1R,2R)-1-(5'-methylfur-3'-yl)propane-1,2,3-triol (MFPT), which had been isolated from Streptomyces sp. strain FV60 with the objective of it being an LAIV candidate. The resulting MFPT-resistant (MFPTr) IAVs possessed attenuated pathogenicity in vitro and in vivo when compared with that of the parent virus (H1N1 subtype, NWS strain). Sequencing analysis revealed that a novel mutation, C490U in ns gene (P164S in NS1), was detected in all MFPTr virus clones tested. Therefore, NS1 might be a main target of MFPT, and it was suggested that the P164S mutation contributed to the attenuated pathogenicity of the mutants. Although the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is one of the targets of NS1, the MFPTr virus suppressed the phosphorylation of Akt when compared with the wild-type (WT) virus. It was suggested that this might lead to the subsequent inhibition of the cleavage of PARP-1 and caspase-3, which is important for the progression of apoptosis. At the same time, nucleoprotein (NP) was found to be retained in the nuclei in MFPTr virus-infected cells while nuclear export of NP was detected in WT virus-infected cells. In addition, the expression levels of interferon-ß transcripts were significantly decreased in MFPTr virus-infected cells. From these results it can be shown that the mutation, NS1P164S, might be one of the key residues to control NS1 function concerning the induction of apoptosis. In conclusion, MFPT induced favorable mutation in the ns gene for the attenuation of IAV, and therefore might provide the novel methodology for preparing LAIVs.

Characterization and biological effects of two polysaccharides isolated from Acanthopanax sciadophylloides.

Two polysaccharides abbreviated ANP and AAP were isolated from the young buds of Acanthopanax sciadophylloides. ANP consisted of L-arabinose, D-mannose, D-glucose and D-galactose in a ratio of ca 1.0:2.6:2.5:1.4 and its weight average molecular weight (Mw) was 1.07×10(4). AAP consisted of L-arabinose, D-galactose and 4-O-methyl-D-glucuronic acid in a ratio of ca 5:10:1, and its Mw was estimated to be 8.40×10(4). ANP was suggested to be an acetylated heteropolysaccharide, whereas AAP was speculated to be a type II arabinogalactan on the basis of structural analysis data. Both polysaccharides were found to stimulate NO production and induce the expression of cytokine mRNAs including IL-1ß, IL-6, IL-10 and TNF-α on RAW264.7 cells. They also induced NF-κB activation in RAW-Blue cells. NO production and NF-κB activation by both polysaccharides were decreased by pretreatment with neutralizing anti-TLR-4 and anti-CD14 antibodies but not with anti-TLR-2, anti-SR-A, anti-CD11c, and anti-Dectin-1 antibodies. Therefore, these immunostimulating effects of ANP and AAP were suggested to be promoted by the interaction through the membrane receptors, TLR-4 and CD14. In addition to immunomodulating effects, ANP showed anti-HSV-2 effects in vitro.

[Chemical constituents from the aerial part of Sibiraea angustata].

OBJECTIVE: To study the chemical constituents from the aerial part of Sibiraea angustata. METHODS: The constituents were isolated by various chromatographic techniques (HP-20 macroporous absorption resin, Sephadex LH-20 gel, RP-MPLC and PHPLC)and their structures were determined on the basis of physicochemical properties and their spectroscopic data,as well as literatures. RESULTS: Eleven compounds were separated and identified as p-methoxycinnamic acid(I), protocatechuic aldehyde(II), quercetin(III), isorhamnetin(IV), quercetin 3-O-beta-D-galactopyranoside (V),9-0-[beta-D-glucopyranoside]-3,4,5-trimethoxy cinnamyl alcohol(VI), syringaresinol-4'-O-beta-D-monoglucoside(VII), ntin(VIII), sibiraic acid(IX), sibiscolacton(X), methyl ferulic acid(XI). CONCLUSION: Compounds I-XIII are isolated from the genus of Sibiraea for the first time.

Mekabu fucoidan: structural complexity and defensive effects against avian influenza A viruses.

Fucoidan from the sporophyll (Mekabu) of brown seaweed Undaria pinnatifida (wakame) is interesting due to its various biological activities. Mekabu fucoidan (Mw ∼ 9 kDa) of this study (MF) was previously isolated and characterized by chemical and separation methods including GPC and methylation analysis (Lee, Hayashi, Hashimoto, Nakano, & Hayashi, 2004). It was found that this fucoidan composed of partially sulphated (DS ∼ 0.72) fucose and galactose at approximately equal amounts. Methylation analyses revealed complex structure of MF. However, it has been still unclear about the linkages between units and substitution patterns. To solve these structural tasks, spectroscopic methods (FTIR, FT Raman and NMR) were used in the analysis of native MF and its deesterified derivatives. According to obtained results, this polysaccharide was defined as O-acetylated sulphated fucogalactan. The defensive effects of MF were evaluated on mice infected with avian influenza A viruses (H5N3 and H7N2 subtypes); its efficacy was determined in reducing viral replication and increasing antibody production. Oral administration of MF resulted in suppressing virus yields. In addition, the production of neutralizing antibodies and mucosal IgA in the animals inoculated with the avian influenza A viruses was significantly increased. These results suggested that MF could be used for the prevention of viral infection.

Topical application of polyethylenimine as a candidate for novel prophylactic therapeutics against genital herpes caused by herpes simplex virus.

Herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) cause genital herpes, which can enhance the acquisition of human immunodeficiency virus. The development of anti-HSV agents with novel mechanisms of action is urgently required in the topical therapy of genital herpes. In this study, the in vitro and in vivo anti-HSV effects of Epomin SP-012(®), a highly cationic polyethylenimine, were evaluated. When the in vitro antiviral effects of SP-012 were assessed, this compound showed potent activity against HSV-1 and HSV-2. It inhibited the attachment of HSV-2 to host cells and cell-to-cell spread of infection in a concentration-dependent manner and exerted a virucidal effect. No SP-012-resistant HSV-2 was found when the virus was successively passaged in the presence of SP-012. In a mouse genital herpes model, topically administered SP-012 inhibited the progression of the disease caused by HSV infection. These data illustrate that SP-012 may be a novel class of HSV inhibitor that would be acceptable for long-term topical application.

Analysis of compounds that interfere with herpes simplex virus-host receptor interactions using surface plasmon resonance.

The entry of herpes simplex virus into host cells involves a complex series of events that require concerted inputs from multiple HSV glycoproteins. Among these glycoproteins, the gD protein of HSV-1 and HSV-2 plays an important role for host receptor binding and membrane fusion. In the present study, we evaluated the ability of different sulfated saccharides to interfere with gD-host receptor (HVEM) interactions using our recently reported molecular assay (Gopinath, S. C. B.; Hayashi, K.; Kumar, P. K. R. J. Virol. 2012, 86, 6732-6744). Initially, we tested the ability of heparan sulfate to interfere with the HVEM-HSV-1 gD interaction and found that heparan sulfate is able to interfere efficiently, with an apparent EC50 of 2.1 µM. In addition, we tested different synthetic sulfated polysaccharides and natural sulfated polysaccharides from an edible alga, Sargassum horneri , after fractionation into different sizes and sulfate and uronic acid contents. Six polysaccharides isolated from S. horneri were found to efficiently interfere with the HVEM-gD interaction. Three others caused moderate interference, and five caused weak interference. These results were confirmed with plaque assays, and good agreement was found with the results of the SPR assay for the identification of compounds that interfere with HVEM-HSV-1 gD binding. These studies suggest that our molecular assay based on surface plasmon resonance is not only useful for the analysis of viral-host protein interactions but is also applicable for the routine screening of compounds to identify those that interfere with the first step of viral entry, thus facilitating the rapid development of novel antiviral compounds that target HSV.

Anti-influenza A virus characteristics of a fucoidan from sporophyll of Undaria pinnatifida in mice with normal and compromised immunity.

Undaria pinnatifida, an edible brown alga, contains fucoidan (FuC), a sulfated polysaccharide, that inhibited the in vitro replication of influenza A virus, and stimulated both innate and adaptive immune defense functions in virus-infected mice. In the present study, the effects of oral administration of FuC were evaluated on influenza virus infection in immunocompetent and immunocompromised mice, where the efficacy of FuC was demonstrated in reducing viral replication, decreasing weight loss and mortality, and prolonging survival. Oral FuC resulted in increased neutralizing antibody production in the mucosa and blood. In contrast, while suppressing virus yields in mice more markedly than FuC, oseltamivir significantly reduced the neutralizing antibody titers in both the mucosa and blood. In immunocompromised mice, drug-resistant viruses frequently recovered after oseltamivir treatment; no resistant viruses were isolated from FuC-treated mice. FuC could be a candidate for the development of new therapeutic options including its combination with neuraminidase inhibitors such as oseltamivir.

Eight New Monoterpene Acylglucosides from Sibiraea angustata.

Chemical investigation of the aqueous extract from the aerial part of Sibiraea angustata, has led to the isolation of eight new monoterpene acylglucosides named sibiraglycoside A-H(1-8), together with two known monoterpenes, Sibiraic acid (9) and Sibiskoside (10). Their structures were elucidated by means of extensive spectroscopic data analysis (including 1D and 2D NMR, HRESIMS experiments), as well as compared with the literature data. The relative configuration was established by NOE studies. In the in vitro bioassay, all the compounds showed moderate hypolipemic effects, among them, compounds 7 and 9, showed distinctive activity on lowering lipid.

Anti-influenza virus effects of elderberry juice and its fractions.

Elderberry (Sambucus nigra L.) has traditionally been used for treating influenza and colds. We evaluated the antiviral effect of concentrated juice of elderberry (CJ-E) on the human influenza A virus (IFV). CJ-E had a relatively strong effect on IFV-infected mice, although its anti-IFV activity was weak in a cell culture system. The in vivo anti-IFV activities of the fractions were determined after separating CJ-E by ultrafiltration and anion-exchange chromatography. Oral administration of the high-molecular-weight fractions of CJ-E to IFV-infected mice suppressed viral replication in the bronchoalveolar lavage fluids (BALFs), and increased the level of the IFV-specific neutralizing antibody in the serum, as well as the level of secretory IgA in BALFs and feces. Fr. II from high-molecular-weight fraction HM, which contained acidic polysaccharides, showed relatively strong defense against IFV infection. We conclude that CJ-E had a beneficial effect by the stimulating immune response and preventing viral infection.

In vitro and in vivo evaluation of a novel antiherpetic flavonoid, 4'-phenylflavone, and its synergistic actions with acyclovir.

The development of therapeutic agents for preventing herpes simplex virus (HSV) infections has become urgently necessary because of the increasing incidence of this virus and its role as a cofactor in the transmission of human immunodeficiency virus infection. We have evaluated the antiviral activities of a series of natural and synthetic flavonoids and found that a synthetic flavonoid, 4'-phenylflavone, showed the highest activity against acyclovir (ACV)-sensitive and ACV-resistant strains of HSV-1, as well as HSV-2, with a selectivity index of 213, 35 and 55, respectively. Although the attachment and penetration of HSV-1 to host cells and the synthesis of viral proteins were not inhibited, the infectivity of the virus and the amount of progeny virus released were reduced by 4'-phenylflavone treatment in a dose-dependent manner. 4'-Phenylflavone plus ACV synergistically inhibited the replication of HSV-1. This flavonoid also showed efficacy in vivo and potentiated the antiherpetic effect of ACV in a mouse model of genital herpes. Our results suggest that 4'-phenylflavone might be useful as a candidate for the development of novel antiherpetic therapeutics.

Structures and anti-HSV-2 activities of neutral polysaccharides from an edible plant, Basella rubra L.

Four neutral polysaccharides (BRN-1, BRN-2, BRN-3 and BRN-4) were isolated from the hot water extract of the aerial part of Basella rubra L. They were found to consist of a large amount of D-galactose (81.0-92.4%) and small amounts of L-arabinose (5.4-7.8%), D-glucose (2.2-11.0%) and mannose (~2.9%). Linkage analysis revealed that all these neutral polysaccharides might be arabinogalactan type I polysaccharides in different molecular weight and chain length. Among them, only BRN-3 showed antiviral activity against herpes simplex virus type 2 (HSV-2) with 50% inhibitory concentration of 55 µg/mL without showing the cytotoxicity up to 2300 µg/mL. Furthermore, the main antiviral target of BRN-3 was shown to be the inhibition of virus adsorption to host cells. This is the first report on the neutral polysaccharide with anti-HSV-2 activity obtained from B. rubra L.

Anti-influenza A virus effects of fructan from Welsh onion (Allium fistulosum L.).

A fructan that acts as an anti-influenza A virus substance was isolated from hot water extract of the green leafy part of a Welsh onion (Allium fistulosum L.). The structure of the fructan was characterised and elucidated by chemical and spectroscopic analyses. The fructan was composed of terminal (21.0%) and 2,1-linked ß-D-Fruf residues (65.3%) with 1,6-linked ß-D-Glcp residues (13.7%). The molecular weight of the polysaccharide and polydispersity was estimated to be 1.5×10(3) and 1.18, respectively. Although the fructan did not show anti-influenza A virus activity in vitro, it demonstrated an inhibitory effect on virus replication in vivo when it was orally administered to mice. In addition, the polysaccharide enhanced the production of neutralising antibodies against influenza A virus. Therefore, the antiviral mechanism of the polysaccharide seemed to be dependent on the host immune system, i.e., enhancement of the host immune function was achieved by the administration of the polysaccharide. From our observations, the fructan from Welsh onions is suggested to be one of the active principles which exert an anti-influenza virus effect.

Lactobacillus plantarum strain YU from fermented foods activates Th1 and protective immune responses.

Lactic acid bacteria (LAB) are known to have effects on immune function. From 203 strains of LAB isolated from fermented foods, we selected a beneficial strain, Lactobacillus plantarum strain YU (LpYU), which has high interleukin (IL)-12-inducing activity in mouse peritoneal macrophages. This activity of LpYU was partially mediated by Toll-like receptor (TLR) 2, but not TLR4 or TLR9. Oral administration of LpYU to ovalbumin (OVA)-immunized mice caused suppression of serum OVA-specific immunoglobulin E (IgE) levels, enhancing interferon (IFN)-γ production from spleen cells in response to OVA. Furthermore, LpYU enhanced natural killer cell activity in spleen cells and the production of IgA from Peyer's patch cells. Because activation of Th1 immune responses and IgA production induce antiviral effects, we evaluated the inhibitory effects of LpYU against the influenza A virus (A/NWS/33, H1N1) (IFV). Oral administration of LpYU suppressed viral proliferation in the lungs and in bronchoalveolar lavage fluids (BALFs). Both levels of IFV-specific secretory IgA in BALF and feces and titers of IFV-specific neutralizing antibody in BALFs and sera were increased. These results indicate that LpYU has a protective effect against IFV replication. We conclude that this strain has a beneficial effect in activating Th1 immune responses and preventing viral infection.

Investigation on traditional medicines of Guarany Indio and studies on diterpenes from Scoparia dulcis.

In interviews on the traditional herbal medicines of Tupi-Guarany Indians at the herbal market of Asuncion and questionnaire from their users, it was clarified that various useful medicinal plants are available in Paraguay and most of them are generally used without drying. In the search for bioactive substances from those plants, a ß-glucuronidase-inhibitory diterpene called scoparic acid A (SA) was isolated from Scoparia dulcis L. together with scoparic acid B, scoparic acid C, and the aphidicolin-like tetracyclic diterpenes scopadulcic acid A (SDA) and scopadulcic acid B (SDB). HPLC analysis of diterpenes in the individual plants of Paraguayan and Asian S. dulcis revealed the presence of three chemotypes based on major component, i.e., SA type, SDB type, and SDX type containing mainly scopadiol and scopadulciol (SDC). SA and SDB were elucidated to be mainly biosynthesized in the leaves via 2-C-methyl-D-erythritol- 4-phosphate pathway, and a leaf organ culture system containing methyl jasmonate 10 µM was found to enhance the production of diterpenes by activation of Ca-signal transduction systems such as calmodulin and protein kinase C. On the other hand, SDB and SDC were found to show multifaceted pharmacological effects such as inhibitory effects on gastric acid excretion, bone resorption, replication of herpes simplex virus type 1 (HSV-1), etc. In addition, SDC was suggested to be applicable to cancer gene therapy using ganciclovir or acyclovir and the HSV-1 thymidine kinase gene called the suicide gene.