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Biomedical subjects

M J Hicks

Publications and source records attributed to M J Hicks.

At least 19 recordsLinked to original sources
PubMed2004

Liposomal enhancement of the antitumor activity of conditionally replication-competent adenoviral plasmids.

Many human tumors have a functional deficiency in p53. Numerous studies have taken advantage of this phenomenon to use a conditionally replication-competent adenovirus (Ad dl1520) that will grow in and lyse tumor cells while sparing normal tissues. However, success has been limited, in part due to difficulties in reaching a sufficiently high proportion of tumor cells. Preexisting or developing immune responses directed toward viral proteins further decrease the efficacy of the approach. We have developed a liposome-encapsulated conditionally replication-competent plasmid based on the dl1520 virus. Like the parent virus, this plasmid generates infectious particles following transfection of p53-defective, but not p53-wild-type tumor cells, but unlike the parent virus it is able to infect CAR-negative tumor cells. The antitumor efficacy of this infectious plasmid was demonstrated in mice with xenografted human tumors, in which it was active after both local and intravenous administration for subcutaneous tumors and following intravenous administration for disseminated malignancy. Activity was retained systemically, even in the presence of neutralizing antibody. Such liposomally encapsulated conditionally replication-competent plasmids may complement the use of conventional viral particles, particularly in settings in which liver uptake of adenoviral vector is undesirable or there are problematic inhibitory effects from humoral immune responses.

Adenoviridae↗
PubMed2002

Plasmablastic lymphoma: an HIV-associated entity with primary oral manifestations.

Plasmablastic lymphoma is a relatively new entity that is considered to be a diffuse large B-cell lymphoma with an unique immunophenotype and a predilection for the oral cavity. We present a 50 year-old HIV-positive, bisexual, white male with a CD4 count 300/mm(3) and a viral HIV-RNA polymerase chain reaction (PCR) load of 237 copies/ml, who developed a painful, purple-red mass in the edentulous area of the maxillary right first molar. Erythematous gingival enlargements of the interdental papillae were seen in three of the dental quadrants. In addition, the patient was being managed with antiretroviral therapy and liposomal doxorubicin for recurrent cutaneous Kaposi's sarcoma (KS). Although oral KS was suspected, the gingival lesions were biopsied because they were refractory to chemotherapy and a lymphoma could not be excluded. Histopathologic examination revealed a lymphoid malignant neoplasm, consistent with a plasmablastic lymphoma. Immunoreactivity with vs38c, CD79a, kappa light chain, and IgG was readily identified in tumor cells; while only focal cells expressed CD20 and LCA (CD45RB). CD56, CD3, lambda light chain, and EMA were non-reactive. EBV was detected in the tumor by Southern hybridization, PCR amplification, in situ hybridization for EBER-1 DNA, and immunohistochemistry for latent membrane protein-1. The same tumor was negative for HHV-8 by PCR. Recognition of plasmablastic lymphoma is important, because it represents an HIV-associated malignancy that predominantly involves the oral cavity, may mimic KS and has a poor prognosis.

Antiretroviral Therapy, Highly Active↗
PubMed2002

Expression of type 2 cystatin genes CST1-CST5 in adult human tissues and the developing submandibular gland.

Type 2 cystatins comprise a class of cysteine peptidase inhibitor presumed to mediate protective functions at various locations, including the oral cavity. Seven cystatin genes are clustered within a 300-kb region of human 20p11.2. "Salivary" cystatins, encoded by CST1, 2, 4, and 5, are present in saliva at significant levels but have also been reported in other secretions, such as tears, suggesting that during their evolution, these genes have acquired mechanisms directing differential tissue-specific expression. However, their patterns of expression, which might also provide additional clues to their individual functions, have not been determined. Gene-specific RNase protection assays were used to examine the qualitative and quantitative distribution of expression of these seven genes within a collection of 23 adult human tissues. The CST3 gene, encoding cystatin C, was expressed at modest levels in all tissues examined. The presumptive pseudogenes CSTP1 and CSTP2 were not expressed at detectable levels in any tissue. The CST1, 2, 4, and 5 genes were expressed in differential, tissue-specific patterns. Expression of CST2 and CST5 was restricted to the submandibular and parotid glands, while CST1 and CST4 were expressed in these tissues and in the lacrimal gland. Immunohistochemistry studies localized expression to the serous-type secretory end pieces. Coexpression of CST1 and CST4 was also observed in the epithelial lining of the gallbladder and seminal vesicle. The CST1 product was detected in the tracheal glands and CST4 in the kidney and prostate. Despite their different adult patterns of expression, analysis of CST1, 2, 4, and 5 mRNA levels in infant submandibular glands demonstrated a coordinate upregulation of expression of between 3.5 and 9 months of age. The patterns of cystatin gene expression are consistent with several proposed oral functions of the salivary cystatins but also suggest they are important in other locations and that, despite their close sequence similarity, they are individually specialized.

Adolescent↗
PubMed2001

The p38 SAPK pathway regulates the expression of the MMP-9 collagenase via AP-1-dependent promoter activation.

The invasive phenotype of cancers critically depends on the expression of proteases such as the M(R) 92,000 type IV collagenase (MMP-9). Several growth factors and oncogenes were found to increase promoter activity and as a consequence protease expression. This frequently requires the activation of the transcription factor AP-1 by signal transduction cascades such as the ERK and JNK pathways. We have previously demonstrated that the tumor promoter TPA can induce MMP-9 expression via a third signaling cascade, the p38 pathway. Considering that TPA is a potent activator of AP-1, we hypothesized that this transcription factor might also be required for p38 pathway-dependent MMP-9 regulation. While dominant negative p38 and MKK-6 mutants reduced MMP-9 promoter activity in CAT assays, a construct encoding an activating mutation in the MKK-6 protein potently stimulated it. This was mediated via 144 bp of the 5'flanking region of the wild-type promoter, which contains an AP-1 site at -79. Both point mutations in this motif and the expression of a c-jun protein lacking its transactivation domain and therefore acting as a dominant negative AP-1 mutant abrogated MKK-6-dependent promoter stimulation. Finally SB 203580, a specific p38 pathway inhibitor, reduced MMP-9 expression/secretion and in vitro invasion of cancer cells. Thus, our results provide evidence that also the third SAPK/MAPK signaling cascade, the p38 signal transduction pathway, stimulates MMP-9 expression in an AP-1-dependent fashion.

Base Sequence↗
PubMed2001

Immotile sperm and infertility in mice lacking mitochondrial voltage-dependent anion channel type 3.

Voltage-dependent anion channels (VDACs), also known as mitochondrial porins, are small channel proteins involved in the translocation of metabolites across the mitochondrial outer membrane. A single channel-forming protein is found in yeast, whereas higher eukaryotes express multiple VDACs, with humans and mice each harboring three distinct channels (VDAC1-3) encoded by separate genes. To begin to assess the functions of each of the three isoforms, the VDAC3 gene was inactivated by targeted disruption in embryonic stem cells. Here we show that mice lacking VDAC3 are healthy, but males are infertile. Although there are normal sperm numbers, the sperm exhibit markedly reduced motility. Structural defects were found in two-thirds of epididymal axonemes, with the most common abnormality being loss of a single microtubule doublet at a conserved position within the axoneme. In testicular sperm, the defect was only rarely observed, suggesting that instability of a normally formed axoneme occurs with sperm maturation. In contrast, tracheal epithelial cilia showed no structural abnormalities. In addition, skeletal muscle mitochondria were abnormally shaped, and activities of the respiratory chain complexes were reduced. These results demonstrate that axonemal defects may be caused by associated nonaxonemal components such as mitochondrial channels and illustrate that normal mitochondrial function is required for stability of the axoneme.

Animals↗
PubMed2001

Dermal and pulmonary inflammatory disease in E-selectin and P-selectin double-null mice is reduced in triple-selectin-null mice.

In the initial phase of an inflammatory response, leukocytes marginate and roll along the endothelial surface as a result of adhesive interactions between molecules on the endothelial cells and leukocytes. To evaluate the role of the 3 selectins (E, L, and P) in leukocyte rolling and emigration, a null mutation for L-selectin was introduced into previously described embryonic stem cells with null mutations in the genes for both E-selectin and P-selectin (E/P double mutants) to produce triple-selectin-null mice (E-selectin, L-selectin, and P-selectin [E/L/P] triple mutants). Triple-selectin homozygous mutant mice are viable and fertile and only rarely develop the severe mucocutaneous infections or pulmonary inflammation characteristic of E/P double-mutant mice. Surface expression of L-selectin was undetectable in triple-mutant mice on fluorescence-activated cell-sorter analysis of peripheral neutrophils. Pathological studies revealed moderate cervical lymphadenopathy and lymphoplasmacytic infiltrate, but these were less extensive than in E/P double-mutant mice. Neutrophil emigration during thioglycolate-induced peritonitis was significantly reduced at 4, 8, and 24 hours (35%, 65%, and 46% of wild-type values, respectively). Intravital microscopy of the cremaster muscle revealed almost no rolling at times up to 6 hours after exteriorization, with or without addition of tumor necrosis factor alpha. The small amount of residual rolling was dependent on alpha(4)-integrin. The occurrence of skin and pulmonary disease in E/P double-mutant mice but not E/L/P triple-mutant mice suggests that deficiency of L-selectin alters the inflammatory response in E/P mutants. (Blood. 2001;98:727-735)

Animals↗
PubMed2001

Lipoblastoma: pathophysiology and surgical management.

BACKGROUND/PURPOSE: Lipoblastoma/lipoblastomatosis is a poorly understood and uncommon soft tissue tumor of infancy and early childhood. Twenty-four patients that presented to a single institution over a 15-year period were reviewed for clinical features and outcome. METHODS: A retrospective review was conducted. RESULTS: Twenty-five cases were identified; 1 chart was not available for review. Fourteen girls and 11 boys with a median age of 20 months (2 months, 10 years) presented with 26 separate tumors. Nineteen were focal and 7 diffuse. The tumors were located on the trunk (n = 13), leg (n = 6), arm (n = 3), and head and neck (n = 4). Five patients (all with diffuse type) had up to 3 recurrences. CONCLUSIONS: Patients with focal lipoblastoma are unlikely to require further surgery after initial resection. Patients with diffuse lipoblastoma (lipoblastomatosis) are likely to have recurrent disease (usually within 2 years) and should undergo close follow-up. Genetic analysis of the specimen will help exclude liposarcoma. Recurrent lesions are best imaged with magnetic resonance imaging to assess extent and plan reconstruction if necessary.

Child↗
PubMed2000

P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice.

The expression of leukocyte and endothelial cell adhesion molecules (CAMs) is essential for the emigration of leukocytes during an inflammatory response. The importance of the inflammatory response in the development of atherosclerosis is indicated by the increased expression of adhesion molecules, proinflammatory cytokines, and growth factors in lesions and lesion-prone areas and by protection in mice deficient in various aspects of the inflammatory response. We have quantitated the effect of deficiency for intercellular adhesion molecule (ICAM)-1, P-selectin, or E-selectin on atherosclerotic lesion formation at 20 wk of age in apolipoprotein (apo) E(-/-) (deficient) mice fed a normal chow diet. All mice were apo E(-/-) and CAM(+/+) or CAM(-/-) littermates, and no differences were found in body weight or cholesterol levels among the various genotypes during the study. ICAM-1(-/-) mice had significantly less lesion area than their ICAM-1(+/+) littermates: 4.08 +/- 0.70 mm(2) for -/- males vs. 5.87 +/- 0.66 mm(2) for +/+ males, and 3.95 +/- 0. 65 mm(2) for -/- females vs. 5.59 +/- 1.131 mm(2) for +/+ females, combined P < 0.0001. An even greater reduction in lesion area was observed in P-selectin(-/-) mice: 3.06 +/- 1.04 mm(2) for -/- males vs. 5.09 +/- 1.22 mm(2) for +/+ males, and 2.85 +/- 1.26 mm(2) for -/- females compared with 5.60 +/- 1.19 mm(2) for +/+ females, combined P < 0.001. The reduction in lesion area for the E-selectin null mice, although less than that seen for ICAM-1 or P-selectin, was still significant (4.54 +/- 2.14 mm(2) for -/- males vs. 5.92 +/- 0.63 mm(2) for +/+ males, and 4.38 +/- 0.85 mm(2) for -/- females compared with 5.94 +/- 1.44 mm(2) for +/+ females, combined P < 0.01). These results, coupled with the closely controlled genetics of this study, indicate that reductions in the expression of P-selectin, ICAM-1, or E-selectin provide direct protection from atherosclerotic lesion formation in this model.

Animals↗
PubMed2000

Oral mucosal melanoma: epidemiology and pathobiology.

The vast majority of healthy individuals have some form of melanocytic lesions with most having several cutaneous melanocytic nevocellular nevi. The incidence of cutaneous melanoma, despite improved prevention and early diagnosis of precursor melanocytic lesions, is on the increase with a projection that one in 75 persons born in the year 2000 will develop cutaneous melanoma in his/her lifetime. With cutaneous melanoma, the number, location and type of nevi, sun exposure and inability to tan, and presence or absence of dysplastic nevi affect transformation to a malignant process. Certain familial factors, syndromes, cytogenetic abnormalities, and mutations in tumor suppressor genes also influence tumor formation. In contrast, mucosal melanoma involving the oral cavity and head and neck regions is not as well understood or characterized. No doubt, this is due to the fact that this subtype of melanoma accounts for less than 1% of all cases. Mucosal melanomas tend to present at a higher stage, are more aggressive, and in a vertical growth phase of disease. A definitive precursor lesion for mucosal melanoma has not been identified; however, atypical melanocytic hyperplasia may represent a proliferative phase before overt tumorigenesis occurs. Melanoma-related antigens, growth factors, and proliferation markers have been identified in cutaneous melanoma, and allow for development of immunotherapy directed against melanoma-associated entities. It is currently possible to evaluate the cytogenetic make-up of precursor melanocytic lesions and frank melanoma, and the constitutional genetic background of individuals at risk for melanoma. No doubt, as concerted investigations of mucosal melanomas of the oral cavity and head and neck evolve, similar factors will be identified which will direct therapy and predict recurrence and survival. In the not too distant future, innovative retroviral transfection, antibodies against specific melanoma-associated factors, vaccination against melanoma, and gene therapy to repair cytogenetic abnormalities and tumor suppressor gene mutations may provide effective therapy and protection against melanomas.

Adult↗
PubMed2000

Oral manifestations of pediatric vertical HIV infection.

To assess the prevalence and prognostic significance of the history of oral manifestations in children with human immunodeficiency virus infection (HIV), a cohort study of 73 children with vertical HIV infection was conducted. The study subjects were examined every 6 months for oral manifestations. The period prevalence of oral manifestations ranged from a low of 1% for submandibular enlargement and 3% for hairy leukoplakia to a high of 36% for xerostomia and 51% for cervical lymphadenopathy. The occurrence of oral manifestations did not change significantly over time from 1995 to 1998. Finally, the odds of occurrence of cervical lymphadenopathy, xerostomia, and oral candidiasis were greater among children in whom these manifestations had been diagnosed in the preceding 6-18 months than in children without prior diagnosis. Oral manifestations are significant clinical outcomes in pediatric vertical HIV infection, particularly for children diagnosed previously with an oral manifestation.

Candidiasis, Oral↗
PubMed2000

Occlusal caries formation in vitro: comparison of resin-modified glass ionomer with fluoride-releasing sealant.

The purpose of this laboratory study was to evaluate caries-like lesion formation in occlusal enamel adjacent to a light-cured resin-modified glass ionomer utilized as a pit and fissure sealant and a conventional light-cured, fluoride-releasing sealant. Fluoride-free prophylaxis was done on occlusal surfaces of 12 caries-free mandibular molar teeth that had not been exposed to the oral cavity. Occlusal surface morphology was examined by SEM on the uncoated specimens. Each tooth was then sectioned into 2 portions buccolingually, producing mesial and distal tooth halve. Occlusal surfaces of mesial tooth halves were prepared for an experimental light-cured resin-modified glass ionomer (RMG) sealant (PH-SE II, ESPE), and for comparison, a light-cured fluoride-releasing pit and fissure (PFS) sealant (Helioseal F, Ivoclar) was placed on occlusal surfaces of the corresponding distal tooth halves. The sealed occlusal surfaces were examined uncoated by SEM to compare RMG and PFS adaptation. After thermocycling in artificial saliva, caries-like lesions were formed in the occlusal surfaces adjacent to RMG and PFS. Longitudinal sections were taken for comparison of lesion formation adjacent to RMG and PFS. Mean lesion depths in occlusal surfaces were 64 +/- 17 mm for RMG, and 116 +/- 27 mm for PFS (p < 0.05, paired t-test). Occlusal lesions terminated at the point where bonding occurred between the occlusal enamel and RMG or PFS. SEM surface topography demonstrated adequate adaptation of the materials with obliteration of the typical pit and fissure surface morphology by both RMG and PFS. While both the resin-modified glass ionomer and fluoride-releasing sealant materials protected the pit and fissure enamel from caries development, the resin-modified glass ionomer reduced the extent of caries involvement in the adjacent unsealed occlusal incline enamel, when compared with the resin sealant.

Bisphenol A-Glycidyl Methacrylate↗
PubMed2000

Resin-modified glass-ionomer restorations and in vitro secondary caries formation in coronal enamel.

OBJECTIVE: The purpose of this laboratory study was to compare the effects of a resin-modified glass ionomer and a resin composite restorative material on secondary caries formation in coronal enamel. METHOD AND MATERIALS: Twelve caries-free molars were sectioned into tooth quarters. Coronal cavities were prepared and then restored with either a resin-modified glass-ionomer material (mesiobuccal and mesiolingual tooth quarters), or a resin composite (distobuccal and distolingual tooth quarters). Caries like lesions were created, and secondary caries was examined by polarized light microscopy following lesion initiation and progression periods. RESULTS: The resin-modified glass-ionomer specimens had significantly shallower primary surface lesions at both the lesion initiation (35% shallower) and progression (45% shallower) periods than did the resin composite specimens. There were significantly fewer wall lesions (3-fold and 2-fold fewer following lesion initiation and progression, respectively) in the resin-modified glass-ionomer group than in the resin composite group. CONCLUSION: Resin-modified glass-ionomer restorations reduce the susceptibility of unrestored adjacent enamel surfaces and cavosurfaces to a constant cariogenic challenge. The caries resistance imparted to the surface enamel and cavosurface is most likely due to the fluoride release from the resin-modified glass-ionomer material.

Composite Resins↗
PubMed2000

Fluoride-releasing sealant and caries-like enamel lesion formation in vitro.

OBJECTIVE: The aim of this laboratory study was to evaluate the effects of a fluoride-releasing pit and fissure sealant (FS) and a conventional non-fluoride-containing pit and fissure sealant (CS) on caries-like lesion formation in enamel. DESIGN: Twelve extracted, macroscopically caries-free human molar teeth underwent fluoride-free prophylaxis and were sectioned into toothquarters. Cavity preparations were placed in buccal and lingual surfaces of the toothquarters, acid-etched and filled with sealant material (per the manufacturer's instructions) as follows: 1) mesiobuccal and mesiolingual quarters--FS (Fissurit-F, VocoChemie); and 2) distobuccal and distolingual quarters--CS (Fissurit, VocoChemie). Prior to caries formation in an acidified gel, the toothquarters were thermocycled (500 cycles) in artificial saliva. Sections were taken following caries initiation (6 week gel exposure) and caries progression (9 week gel exposure), and examined by polarized light microscopy to determine mean primary surface lesion depth and presence or absence of wall lesions. RESULTS: Mean surface lesion depths were significantly different between FS and CS groups following caries initiation (FS = 119 microns; CS = 157 microns, p < 0.05, paired t-test) and progression (FS = 169 microns; CS = 221 microns, p < 0.05, paired t-test). Wall lesions were reduced in FS (14% initiation; 25% progression) when compared with CS (19% initiation; 35% progression); however, this was not significantly different (p > 0.05, paired t-test). CONCLUSION: A pit and fissure sealant containing releasable fluoride provided a caries inhibiting effect with a significant reduction in lesion depth in the surface enamel adjacent to the fluoride-releasing sealant and a tendency toward reduction in the frequency of wall lesions. CLINICAL SIGNIFICANCE: Fluoride release by pit and fissure sealants may provide additional protection against caries formation in cuspal incline enamel and smooth surfaces adjacent to sealed pits and fissures, and act as a fluoride reservoir with long-term release of fluoride into the immediately adjacent oral environment.

Acid Etching, Dental↗
PubMed1999

Chronic inflammatory disease alters adhesion molecule requirements for acute neutrophil emigration in mouse skin.

Mutant mice triply deficient in ICAM-1, E-selectin, and P-selectin did not develop the neutrophilic skin lesions that spontaneously arise in mutants doubly deficient in E-selectin and P-selectin. Thus, ICAM-1 is essential to skin disease resulting from endothelial selectin deficiency. During experimental dermatitis, acute neutrophil emigration was completely prevented in young mice deficient in both selectins (E/P and E/P/I mutants). However, older E/P mutants with spontaneous skin lesions displayed an endothelial selectin-independent pathway for acute neutrophil emigration. In contrast, emigration remained compromised in E/P/I mutants and CD18 mutants regardless of age or lesions. Experimentally induced chronic lesions elicited this pathway for acute emigration in young E/P mutants. Thus, an endothelial selectin-independent pathway for acute neutrophil emigration is induced in E/P mice by chronic inflammation at distant sites, and this pathway may contribute to skin disease resulting from endothelial selectin deficiency.

Aging↗
PubMed1999

Gastrointestinal autonomic nerve tumors in the pediatric population: a report of four cases and a review of the literature.

BACKGROUND: Gastrointestinal autonomic nerve tumors (GANTs) are a subpopulation of gastrointestinal stromal tumors (GISTs) that are characterized by ultrastructural features resembling enteric autonomic nerve cells, without epithelial, Schwannian, or smooth muscle differentiation. Delineation of the clinicopathologic features of GANT in the pediatric population is lacking. METHODS: The clinicopathologic and outcome data for four pediatric patients with GANT are presented. The data from these patients and four previously reported pediatric patients are summarized and compared with data for GANT in adults. RESULTS: All four cases occurred in females at a mean age of 12.5 years. The primary tumor site was the stomach in all cases, and the mean tumor size was 6.3 cm. Immunocytochemical and ultrastructural examination were essential in distinguishing GANT from GIST in all cases by identifying features of neural origin (neuron specific enolase in all four cases, NFP in three cases, S-100 in two cases, dense core neurosecretory granules in all four cases, and neuritelike processes in all four cases), while failing to identify features of myogenic origin (no desmin, smooth muscle actin, myofilaments, or dense bodies were found in any of the cases). Primary treatment was surgical, with chemotherapy administered to 1 patient at the time of recurrence. All patients are alive after a mean follow-up of 60 months (range, 8 months to 9 years). CONCLUSIONS: Similarities of pediatric GANT to GANT in adults include the need for a high index of suspicion for diagnosis; comparable histopathologic, immunohistochemical, and ultrastructural features; and surgery as the primary therapy. Distinguishing features in children may be a prevalence among females in the second decade, a predominance of smaller gastric tumors, and a positive prognostic value of younger age.

Adolescent↗
PubMed1999

Malignant chondroblastoma presenting as a recurrent pelvic tumor with DNA aneuploidy and p53 mutation as supportive evidence of malignancy.

We report a rare case of malignant chondroblastoma, which presented in a 47-year-old man as a recurrent tumor, 18 years following wide excision of a typical pelvic chondroblastoma. Radiologic studies of the recurrent tumor showed a large, lytic, destructive lesion of the right pelvic bones and femur, with a pathologic fracture of the latter, a large pelvic soft tissue mass, and multiple pulmonary metastases. Biopsy tissue showed typical features of chondroblastoma, but also increased nuclear atypia, hyperchromasia, and pleomorphism, compared to the original tumor, and, most significantly, abnormal mitotic figures. Immunohistochemical studies of the recurrent tumor revealed p53 mutation and extensive proliferative activity, and flow cytometric studies showed DNA aneuploidy, none of which was present in the original tumor. The patient received chemotherapy and radiation, but died of disease eight months after presentation. We also review chondroblastoma in general, to assign this unusual lesion to a tumor subtype.

Aneuploidy↗
PubMed1999

PD 098059, an inhibitor of ERK1 activation, attenuates the in vivo invasiveness of head and neck squamous cell carcinoma.

Increased mortality of patients with oral cancer largely reflects the local and regional spread of the disease. The invasiveness of these tumours requires hydrolases which are regulated through AP-1-dependent transcriptional mechanisms. Since the amount/activity of transcription factors bound to the AP-1 motif are regulated partly through the extracellular signal-regulated kinases (ERK1/ERK2), we determined the effect of PD 098059, an inhibitor of ERK1/ERK2 activation, on the in vivo invasiveness of a human squamous cell carcinoma cell line (UM-SCC-1) derived from the oral cavity. We utilized the floor of mouth musculature consisting of the mylohyoid, geniohyoid and genioglossus muscle (which are sequentially arranged), as a natural barrier to assess tumour spread in vivo in the nude mouse. Mice were inoculated with tumour cells superficial to the mylohyoid muscle. After 18 days, tumours were injected with either empty liposomes (control) or liposomes containing 5 microM PD 098059 and, after an additional 22 days, the jaws of mice examined histologically. Highly infiltrative tumours, which had penetrated the genioglossus muscle, were evident in 10/12 control mice. In contrast, in 9/12 mice in which the tumours were injected with PD 098059, tumours did not extend beyond the mylohyoid or geniohyoid muscles. Tumours penetrated bone nutrient canals in 7/12 control mice but in only 3/12 PD 098059-treated mice. Neurotropism, characteristic of aggressive oral squamous cell carcinoma, was evident in 6/12 control mice but was completely abolished (0/12 mice) in the PD 098059-treated mice. Using a staging system based on the muscle layer involved, neurotropism, as well as bone involvement, we found the inhibition of invasion to be statistically significant (P < 0.01). The reduced invasiveness of the PD 098059-liposome-treated oral cancers was associated with diminished 92-kDa type IV collagenase and ERK1/ERK2 activities but was not a consequence of a slower tumour growth rate. This is the first study to demonstrate reduced in vivo invasiveness of a malignancy brought about by an inhibitor of ERK1/ERK2 activation. These results raise the exciting possibility that second generation PD 098059 congeners may reduce the spread of the disease in patients afflicted with oral cancers.

1,2-Dipalmitoylphosphatidylcholine↗