I heard that a group in Ottawa was also working on a viral cancer therapeutic. Does anyone know of this group?
In the meantime, here are a bunch of abstracts on other potential viral cancer therapies: (apologies for the format)
Cancer Res 2000 Jan 15;60(2):334-41 Prostate-specific antigen promoter/enhancer driven gene therapy for prostate cancer: construction and testing of a tissue-specific adenovirus vector. Latham JP, Searle PF, Mautner V, James ND CRC Institute for Cancer Studies, University of Birmingham, United Kingdom.
A range of luciferase reporter vectors was constructed, incorporating
5'-flanking sequences from the prostate-specific antigen (PSA), human glandular kallikrein 2 (hKLK2), and cytomegalovirus
(CMV) promoters for expression control. Tissue specificity was evaluated in the PSA-positive line LNCaP and PSA-negative cells
from different tissues of origin (CoLo320, DG75, EJ, A2780, and Jurkat). The minimal 628-bp PSA and hKLK2 promoters showed
only low-level expression in either PSA-positive or PSA-negative cells and showed no increase with the addition of androgen.
Tandem duplication of the PSA promoter slightly increased expression in PSA-positive LNCaP cells. The addition of CMV
enhancer sequences upstream of a single PSA or hKLK2 promoter substantially but nonspecifically increased luciferase expression in
all cell lines tested. However, placing a 1455-bp PSA enhancer sequence upstream of either the PSA or hKLK2 promoters increased
expression 20-fold in the PSA-positive cell line LNCaP but not in the PSA-negative lines. Tandem duplication of the PSA
enhancer increased expression to approximately 50-fold higher than either promoter alone while retaining tissue-specific control.
The level of expression was reduced by the addition of a third copy of the PSA enhancer. Expression from all enhancer constructs
was increased 100-fold above basal levels when induced with the androgen dihydrotestosterone, with the PSA-based constructs
consistently exhibiting roughly twice the level of expression of the hKLK2-based constructs at all androgen concentrations.
Adenovirus vectors were produced in which either enhanced green fluorescent protein or nitroreductase could be expressed from the
optimized PSA double enhancer-promoter construct and evaluated in LNCaP cells and the bladder-derived line EJ. Control vectors
with the CMV promoter gave good levels of expression in both cell lines, whereas the PSA constructs only produced detectable levels
of protein in the LNCaP cells as assessed by fluorescence of enhanced green fluorescent protein or by Western blotting of
nitroreductase. LNCaP but not EJ cells were selectively sensitized to the prodrug CB1954 following infection with
Ad-PSA(EEP)-NR. The PSA-based nitroreductase virus produced comparable amounts of nitroreductase and sensitization to
CB1954 approaching that of the CMV-driven virus. Plasmid and adenovirus constructs combining PSA enhancer and promoter
sequences demonstrate selective expression of linked genes in PSA-positive cells. The expression is induced by androgen and gives
therapeutically relevant levels of effector proteins. PMID: 10667585, UI: 20129047
---------- Cancer Res 1999 Dec
1;59(23):5896-901 Combination therapy with the farnesyl protein transferase inhibitor SCH66336 and SCH58500 (p53 adenovirus) in preclinical cancer models. Nielsen LL, Shi B, Hajian G, Yaremko B, Lipari P, Ferrari E, Gurnani M, Malkowski M, Chen J, Bishop WR, Liu M Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
SCH66336 is a p.o.-active,
farnesyl protein transferase inhibitor. SCH66336 inhibits farnesylation of RAS and other proteins in tumor cells and suppresses
tumor growth in human xenograft and transgenic mouse cancer models in vivo. SCH58500 is a replication-deficient, recombinant
adenovirus, which expresses the human p53 tumor suppressor. In preclinical models, SCH58500 has therapeutic efficacy against a
wide range of human tumor types containing nonfunctional p53 and enhanced activity in combination with many chemotherapeutic
drugs. Here we report that combination therapy with SCH66336 and SCH58500 has synergistic or additive antiproliferative effects on
a panel of tumor cells lines in vitro. The efficacy of the three-drug combination of SCH66336, SCH58500, and paclitaxel was also
examined in vitro. Each two-drug interaction displayed such marked synergy, the addition of a third drug to the statistical model
could only yield additivity. Greater combined efficacy for SCH66336 and SCH58500 was also observed in vivo in the DU-145 human
prostate and wap-ras/F transgenic mouse cancer models. PMID: 10606231, UI: 20072247
---------- Cancer Res 1999 Sep
1;59(17):4200-3 Published erratum appears in Cancer Res 2000 Feb 15;60(4):1150 The addition of adenovirus type 5 region E3
enables calydon virus 787 to eliminate distant prostate tumor xenografts. Yu DC, Chen Y, Seng M, Dilley J, Henderson DR Calydon,
Inc., Sunnyvale, California 94089, USA.
CV787, a novel highly prostate-specific replication-competent adenovirus with improved
efficacy, was constructed. CV787 contains the prostate-specific rat probasin promoter, driving the adenovirus type 5 (Ad5) E1A
gene, and the human prostate-specific enhancer/promoter, driving the E1B gene. To improve efficacy, we constructed CV787 such
that it also contains the entire Ad5 E3 region. CV787 replicates in prostate-specific antigen (PSA)+ cells as well as wild-type
adenovirus, but in PSA- cells, CV787 replicates 10(4)-10(5) times less efficiently. CV787 destroys PSA+ prostate cancer cells
10,000 times more efficiently than PSA- cells. Incorporation of the Ad5 E3 region significantly improves the target cell killing
ability or efficacy of CV787. In nu/nu mice carrying s.c. LNCaP xenografts, a single i.v. tail vein injection of CV787 eliminates
300-mm3 tumors within 4 weeks. CV787 could be a powerful therapeutic for human metastatic prostate cancer. PMID: 10485454,
UI: 99413464
---------- Cancer Res 1999 May 1;59(9):2055-8 Replication-competent, nonneuroinvasive genetically engineered
herpes virus is highly effective in the treatment of therapy-resistant experimental human tumors. Advani SJ, Chung SM, Yan SY,
Gillespie GY, Markert JM, Whitley RJ, Roizman B, Weichselbaum RR Department of Radiation and Cellular Oncology, The
University of Chicago Hospitals Duchossois Center for Advanced Medicine, Illinois 60637, USA.
A genetically engineered,
nonneurotropic herpes simplex virus (R7020) with a proven safety profile in both animals and humans was found effective in the
treatment of large xenotransplanted tumors arising from a radiation- and chemotherapy-resistant human epidermoid carcinoma and
a hormone-refractory prostate adenocarcinoma. R7020 replicated to high titer and caused rapid regression of the human tumor
xenografts. Tumor destruction was accelerated in animals given both R7020 and fractionated ionizing radiation. Tumors arising from
cells surviving one treatment with R7020 were fully susceptible to a second dose of virus. We conclude R7020 is an effective
antitumor agent for non-central nervous system tumor xenografts with an excellent safety profile. PMID: 10232586, UI: 99247546
---------- Cancer Res 1999 Apr 1;59(7):1498-504 Identification of the transcriptional regulatory sequences of human kallikrein
2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy.
Yu DC, Sakamoto GT, Henderson DR Calydon, Inc., Sunnyvale, California 94089, USA.
Human glandular kallikrein (hK2) and
prostate-specific antigen (PSA) are related members of the human kallikrein gene family. The genes for hK2 and PSA are expressed
predominately in the prostate, are transcriptionally up-regulated by androgens, and share 78% homology. Previously, one functional
androgen response element was identified within the proximal promoter (-324 to +33 relative to the cap site) of the hK2 gene. To
detect additional upstream regulatory elements, the 12.3 kbp between the PSA gene and 5' to the hK2 gene were amplified by PCR
and linked to a promoterless firefly luciferase reporter gene. Transient transfection experiments showed an androgen-dependent
enhancer, located between -3.4 and -5.2 kb upstream of the transcription start site of the hK2 gene. This hK2 enhancer increased
luciferase expression 100-fold in the presence of the testosterone analogue R1881. The hK2 enhancer contains an androgen response
element that lost activity when mutated. The hK2 enhancer/promoter demonstrated activity in PSA(+) LNCaP cells whereas the
enhancer/promoter was inactive in PSA(-) 293, A549, HBL100, HUH-7, LoVo, MCF-7, OVCAR-3, and PC-3 cells. Insertion of
the hK2 enhancer/promoter into adenovirus to drive the E1A genes of adenovirus type 5 (Ad5) created an attenuated replication
competent adenovirus variant Calydon virus (CV) 763, which replicates similarly to wild-type adenovirus in prostate tumor cells but
is attenuated in nonprostate tumor cells. In addition, CV764, an adenovirus variant containing the previously cloned
prostate-specific enhancer (to drive the Ad5 E1A genes) and the hK2 enhancer/promoter (to drive the Ad5 E1B genes) was
constructed. CV764 is significantly attenuated and has a high therapeutic index with a cell specificity of 10,000:1 for PSA(+) LNCaP
cells, compared to ovarian cancer OVCAR-3 cells and SK-OV-3 cells and PA-1 cells. CV764 is also highly attenuated in primary
human microvascular endothelial cells. PMID: 10197620, UI: 99211477 ----------
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