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Biomedical subjects

Patrick Guinan

Publications and source records attributed to Patrick Guinan.

14 recordsLinked to original sources
PubMed2006

Synthesis of branched antisense oligonucleotides having multiple specificities. Treatment of hormone insensitive prostate cancer.

Antisense oligonucleotides (oligos) directed against transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR), have demonstrated in vitro and in vivo efficacy against both the PC-3 and LNCaP prostate tumor models. In an attempt to increase the efficiency of these oligos a new type of antisense compound called a bispecific oligo has been evaluated in vitro both alone and in combination with traditional chemotherapeutic agents. These bispecifics, which were first proposed in this journal in 2004, include binding sites for both TGF-alpha and EGFR along the same stretch of complementary DNA. Such bispecifics are able to deliver essentially two antisense activities in an equal molar ratio and can be directed against mRNA encoding proteins of different biochemical pathways. The first bispecifics were developed against two proteins regulating a single autocrine loop. Subsequent bispecifics have been developed which target both EGFR and the apoptosis regulating protein bcl-2. Bispecific activity of a single linear sequence oligo has already been shown to have efficacy. To further develop this multispecific approach, we now propose a branched antisense compound, again, having multiple binding site activities (to complementary sequenced mRNA). Active oligos would be attached to a fat soluble backbone which might enhance targeting and also intracellular entry, release and activity. Such a structure would also permit the customization of these branched forms to include oligos targeting specific proteins related to the growth of various tumor types. Problems associated with the development of antisense oligos have included both membrane solubility and specific targeting. By designing this branched form of antisense structure, multiple activities can be retained (added), solubility improved and delivery enhanced. Such a new formulation would include several antisense oligos covalently bound to and branching off from a lipid-like backbone. An elongated hydrocarbon chain would increase fat solubility and would permit oligo incorporation into nanoparticles or liposome derived delivery vehicles. Specific delivery of oligos could also be enhanced by the tendency of these nanoparticle or liposomal microbubbles to be disrupted under the influence of ultrasonic waves beamed at the targeted tissue.

Cell Line, Tumor↗
PubMed2006

Who is my patient?

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American Medical Association↗
PubMed2005

Construction of a bispecific antisense oligonucleotide containing multiple binding sites for the treatment of hormone insensitive prostate tumors.

Antisense oligonucleotides (oligos) have demonstrated efficacy for the treatment of various cancers, infectious diseases and metabolic disorders. While most studies have utilized single oligos either administered alone, or more recently in combination therapy with other drugs, some investigators have administered more than one oligo in a combined administration or have designed oligos which target multiple proteins (those which share mRNA sequence homology). Antisense oligos inhibit mRNA translation through complementary base pair binding, often about the AUG initiation codon. This inhibition is further enhanced through destruction of the mRNA:oligo hybrid by RNAse H. Construction of an oligo with multiple binding sites located about the respective mRNA initiation codons could simultaneously block translation of more than one protein, even those unrelated in sequence. Such binding could produce a complex mRNA:oligo hybrid more prone to degradation and clearance. Furthermore, such a formulation would increase oligo specific activity and cellular uptake, reduce toxicity, and stabilize at 1:1 the ratio between multiple oligo active sites which otherwise must be comparably delivered (in amount) and individually targeted. The activity of these newly constructed oligos could be tested in both in vitro and in vivo prostate tumor models, utilizing the hormone sensitive LNCaP and the hormone insensitive PC-3 lines. In vitro testing would evaluate oligos administered either alone or in combination with other chemotherapeutics. In vivo testing would administer the oligos to tumors carried in athymic nude mice by either intratumoral inoculation or by using a diffusion pump. Antisense oligos which target proteins associated with growth factors or their receptors, could have a role in the treatment of human prostate cancers when administered with hormone deprivation therapy, or against tumors which have already become hormone insensitive. In the later case, such treatment could form the basis of a second tier of therapy based upon growth factor deprivation.

Androgens↗
PubMed2005

Correlation between PSMA and VEGF expression as markers for LNCaP tumor angiogenesis.

Our aim is the identification and correlation of changes in tumor-associated protein expression which results from therapy. LNCaP tumors, excised from nude mice treated either by orchiectomy or with the chemotherapeutic agent paclitaxel, were evaluated for the expression of proteins and receptors associated with growth, differentiation, and angiogenesis using immunohistologic procedures. Compared to untreated control tumors, both treatments reduced the expression of vascular endothelial growth factor (VEGF), prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), androgen receptor (AR), and epidermal growth factor receptor (EGFR). The effect of paclitaxel treatment on AR expression was the most significant (P = .005). Of particular interest was identifying a significant correlation (P < .000801) between PSMA and VEGF expression regardless of treatment modality. These altered expressions suggest that PSMA may also be a marker for angiogenesis and could represent a target for deliverable agents recognizing either prostatic tumors or endothelial development. Cell surface PSMA would then present a unique target for treatment of patients early in their development of prostatic metastases.

Journal Article↗
PubMed2004

Synergistic effects of combination therapy employing antisense oligonucleotides with traditional chemotherapeutics in the PC-3 prostate cancer model.

Combination therapy including antisense oligonucleotides (ODNs) with traditional chemotherapeutic agents offers potential benefits by increasing the effectiveness of the chemotherapeutics, reducing their effective dosage, and simultaneously reducing toxicity. Previously we have reported that antisense ODNs specific for transforming growth factor-alpha (TGF-alpha) and its binding site, the epidermal growth factor receptor (EGFR) (MR1 and MR2, respectively), are effective against the PC-3 in vitro and in vivo prostate cancer models. In this series we evaluated these antisense ODNs in various combinations and treatment cycles with paclitaxel (Taxol), cyclophosphamide (Cytoxan), mitoxantrone, carboplatin, cisplatin, and oxaliplatin in order to identify synergistic effects.We found that when either of the ODNs were simultaneously administered with Taxol, no synergistic activity was noted. However, when sequentially administered in a series 1 d apart, a pretreatment with the ODN directed against TGF-alpha (6.64 microm) followed by Taxol (5 nm) had significantly (p <0.001) greater activity than these agents similarly administered in the reverse order or simultaneously. When Cytoxan was administered in sequence with both ODNs significantly increased growth inhibition was obtained compared to when Cytoxan was administered alone. A 1 d treatment of PC-3 cells with Cytoxan followed the next day with MR1 was significantly more effective (p <0.0001). The reverse order, a pretreatment with MR1 followed by Cytoxan, also resulted in significant additional inhibition (p=0.0004). Similarly sequenced, MR2 followed by Cytoxan, was also significantly more effective (p=0.0014) than Cytoxan treatment alone. For mitoxantrone, which was administered in combination therapy with ODNs: mitoxantrone with MR1 was significantly more inhibitory than the combination of both MR1 and MR2 ODNs (p=0.006) and also mitoxantrone administered alone (p=0.0012). Mitoxantrone administered with MR1 was not significantly different from mitoxantrone given in combination with MR2. Although mitoxantrone and MR2 was statistically (p=00015) more inhibitory than mitoxantrone alone, this combination was barely more effective (p=0.04) than the MR1 ODN administered alone.

Antineoplastic Agents↗
PubMed2003

Inhibition of PC-3 prostate cancer cell growth in vitro using both antisense oligonucleotides and taxol.

Antisense oligonucleotides (oligos) directed against mRNA-encoding transforming growth factor-alpha (TGF-alpha) and the epidermal growth factor receptor (EGFR) have demonstrated in vitro and in vivo efficacy against prostate cancer tumor models. However, many therapeutic agents have increased effectiveness when given in combination with other more established agents. We evaluated the effectiveness of two oligos (3.32 and 6.64 microM/L) known to have significant activity against the PC-3 prostate cell line in combination therapy with the chemotherapeutic agent paclitaxel (Taxol) (2.5 and 5.0 nm). Therapy was evaluated when oligos and Taxol were administered either as (1) single agents, (2) simultaneously in a combined therapy, or (3) sequentially, a form of combination therapy with both agents being administered in a series. We found that when either of the two oligos were given simultaneously with Taxol, no synergistic activity was noted. However, when sequentially administered in a series 1 d apart, a pretreatment with the antisense directed against TGF-alpha (6.64 microM/L) followed by Taxol (5 nm) had significantly greater activity than these agents similarly administered in the reverse order or simultaneously.>

Antineoplastic Agents, Phytogenic↗
PubMed2002

Toward a more natural medicine.

Modern science and culture attempt to dominate and control nature. Unfortunately contemporary medicine has followed this lead. Traditionally religion has recognized the order and goodness in the natural order and has encouraged followers to comply with the rules of nature. Medicine, from Hippocratic times, has viewed the physician as an assistant to nature. Contemporary medicine, while employing modern science, would be well advised to also recognize the healing effects of religion's admonition to acknowledge and respect the wisdom of nature.

Codes of Ethics↗
PubMed2002

Bioterrorism, embryonic stem cells, and Frankenstein.

The stem cell controversy raises a fundamental question for humankind. Does science have a right to pursue knowledge whatever the cost? Our Enlightenment culture says yes. However, human history and literature are sending warning signals. Ethical issues impact the "knowledge for its own sake" imperative, and must be addressed.

Biomedical Research↗
PubMedDate not supplied

Two constructed antibody-derived delivery vehicles for targeting oligodeoxynucleotides to prostate tumors expressing prostate specific antigen.

We evaluated the ability of antibody-derived delivery vehicles (DVs) to direct synthetic biotinylated oligodeoxynucleotides (ODNs) to prostate tumors in vitro. A monoclonal mouse antibody raised against prostate-specific antigen (PSA) was modified by two approaches to produce either: (1) a bispecific delivery vehicle recognizing both PSA and biotin (DV(Hc)), or (2) an avidin-conjugated anti-PSA delivery vehicle (DV(PSA)). Immunoreactivity of the DVs and their ability to form complexes were tested in vitro. Although both DVs retained immunoreactivity and were able to form complexes with biotinylated ODNs, the avidin modification method was more efficient. This method may be useful for selective delivery of antisense ODNs to prostate tumors.

Animals↗
PubMedDate not supplied

siRNA is not more effective than a first generation antisense oligonucleotide when directed against EGFR in the treatment of PC-3 prostate cancer.

siRNA specifically directed against the epidermal growth factor receptor (EGFR) was compared to the previously described and effective MR2 oligo (also specific for EGFR) in a total of six comparative studies utilizing the chemotherapeutic agents Taxol, cisplatin and Cytoxan and the PC-3 prostate tumor line. When Taxol was administered in combination with either MR2 or siRNA, the MR2 was significantly more effective (p = 0.000277) against PC-3 cells incubated for 24 h in their presence. In a sequential study in which a 24-h Taxol treatment was followed with either MR2 or siRNA for an additional 24 h, or in the reverse order where MR2 or siRNA was followed by Taxol, no significant differences were found. When cisplatin was similarly administered in combination with either MR2 or the siRNA, no significant differences in inhibition were found. In a subsequent study, in which a 24-h treatment with either MR2 or siRNA was followed by cisplatin for an additional 24 h, again no significant differences were found. Lastly, in a series of sequential administrations including Cytoxan the following was found. PC-3 cells treated for 24 h with Cytoxan followed by either MR2 or siRNA produced similar inhibition. When the cycle was reversed, with MR2 or siRNA treatment followed by Cytoxan, both treatments were again inhibitory, however the initial treatment with MR2 was significantly more effective (p = 0.026095). We conclude that, although siRNA against EGFR has efficacy against the PC-3 line when administered either alone vs untreated controls, with Taxol vs Taxol alone, or with cisplatin vs cisplatin alone, it is not more effective than the better characterized MR2 oligo.

Adenocarcinoma↗