Evidence Of Systemic Toxicity Research Articles

Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells.

We report the antitumor effects of nitric oxide (NO) releasing derivatives of the PARP-1 inhibitor olaparib (1). Compound 5b was prepared by coupling the carboxyl group of 3b and the free amino group of arylated diazeniumdiolated piperazine 4. Analogue 5a has the same structure except that the F is replaced by H. Compound 13 is the same as 5b except that a Me2N–N(O)=NO– group was added para and ortho to the nitro groups of the dinitrophenyl ring. The resulting prodrugs are activated by glutathione in a reaction accelerated by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancers. This metabolism generates NO plus a PARP-1 inhibitor simultaneously, consuming reducing equivalents, leading to DNA damage concomitant with inhibition of DNA repair, and in the case of 13 inducing cross-linking glutathionylation of proteins. Compounds 5b and 13 reduced the growth rates of A549 human lung adenocarcinoma xenografts with no evidence of systemic toxicity.

Safety of Cidofovir by Intratympanic Delivery Technique

Congenital cytomegalovirus (CMV) infection is one of the most common infectious causes of congenital sensorineural hearing loss. To date, a safe and effective therapy for CMV-induced hearing loss does not exist. We hypothesize that the antiviral cidofovir (CDV) can be delivered to the inner ear via intratympanic (IT) injections to safely and effectively mitigate CMV-induced hearing loss. To evaluate the safety of CDV IT injections, weanling guinea pigs with normal hearing were injected intratympanically with 3 mg or 5 mg concentrations of CDV and compared to control animals injected with sterile saline. A separate group of weanling guinea pigs were inoculated with CMV and a subset of this group was treated with CDV following inoculation. The 3 mg/ml and 5 mg/ml CDV concentrations resulted in hearing loss following IT injection into uninfected animals. No signs of inflammation or toxicity were noted on histologic analysis and there was no evidence of systemic toxicity in serology. Hearing loss induced as a result of guinea pig CMV infection recovered by day 21 in animals treated with IT injections of 5 mg/ml CDV. We provide promising evidence demonstrating both the efficacy and safety of IT CDV in the guinea pig animal model. This research further establishes a sound framework upon which ongoing investigations into drug delivery mechanisms for CMV-induced hearing loss will be based.

Suppression of Prostate Epithelial Proliferation and Intraprostatic Progrowth Signaling in Transgenic Mice by a New Energy Restriction-Mimetic Agent

Cells undergoing malignant transformation often exhibit a shift in cellular metabolism from oxidative phosphorylation to glycolysis. This glycolytic shift, called the Warburg effect, provides a mechanistic basis for targeting glycolysis to suppress carcinogenesis through the use of dietary caloric restriction and energy restriction-mimetic agents (ERMA). We recently reported the development of a novel class of ERMAs that exhibits high potency in eliciting starvation-associated cellular responses and epigenetic changes in cancer cells though glucose uptake inhibition. The lead ERMA in this class, OSU-CG5, decreases the production of ATP and NADH in LNCaP prostate cancer cells. In this study, we examined the effect of OSU-CG5 on the severity of preneoplastic lesions in male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. Daily oral treatment with OSU-CG5 at 100 mg/kg from 6 to 10 weeks of age resulted in a statistically significant decrease in the weight of urogenital tract and microdissected dorsal, lateral, and anterior prostatic lobes relative to vehicle controls. The suppressive effect of OSU-CG5 was evidenced by marked decreases in Ki67 immunostaining and proliferating cell nuclear antigen (PCNA) expression in the prostate. OSU-CG5 treatment was not associated with evidence of systemic toxicity. Microarray analysis indicated a central role for Akt, and Western blot analysis showed reduced phosphorylation and/or expression levels of Akt, Src, androgen receptor, and insulin-like growth factor-1 receptor in prostate lobes. These findings support further investigation of OSU-CG5 as a potential chemopreventive agent.

Safety and efficacy of dendritic cell immunotherapy with ad-GMCAIX in an immunocompetent preclinical tumor model of renal cell carcinoma.

e13045 Background: We have previously reported the successful ex vivo generation of hCAIX-specific cytotoxic T lymphocytes (CTLs) by adenoviral (Ad) transduction of the GMCAIX fusion protein in dendritic cells (DC). We then produced GMP-grade material (NIH-RAID program, NSC 740833). Now we test, for the first time, the in vivo anti-tumor activity of DC-Ad-GMCAIX against renal cell carcinoma (RCC) in a unique immunocompetent mouse tumor model. Methods: Tumor growth inhibition and specificity were studied in BALB/c mice s.c. transplanted with either syngeneic RENCA cells transduced with hCAIX (URCAIX) or with non-hCAIX-expressing RENCA cells (RENCA). In a tumor prevention model, cohorts of mice were first immunized s.c. twice with DC-Ad-GMCAIX, DC-Ad-null, or no DCs, followed by tumor challenge with s.c. transplantation of URCAIX or RENCA cells. In an intervention model, tumors were first established and then immunotherapy was employed. Tumor volume and body weight were regularly assessed. Partial necropsy, immunohistochemistry of harvested tumors, and complete blood count were performed at termination of each study. Results: In the prevention model, URCAIX tumor growth was specifically and significantly inhibited for 15 days (p<0.0001). At termination, median growth inhibition reached 79% (113 vs. 531 mm3) and half of the mice remained tumor-free. In the intervention model, DC-Ad-GMCAIX-treated mice showed specific and significant growth inhibition of URCAIX tumors for 8 days (p<0.0018) with a median growth inhibition reaching 60% (487 vs. 1,205 mm3). The threshold of 15% weight loss was delayed in the therapeutic groups of both models (p<0.0167). No treatment-related weight loss or organ toxicity was observed. hCAIX staining was absent or minimally present in URCAIX-tumors that evaded DC-Ad-GMCAIX therapy. Conclusions: DC-Ad-GMCAIX therapy in a novel immunocompetent mouse model demonstrated, for the first time, both tumor prevention and growth inhibition of established RCC tumors without evidence of systemic toxicity. These studies form the basis for first-in-human clinical trial in patients with advanced RCC.

Index of Suspicion * Case 1: Fever, Barking Cough, Stridor, and Rash in an Infant * Case 2: Erythematous Papulovesicular Rash in a 3-month-old Girl * Case 3: Vomiting and Unrelenting Headaches in a 5-year-old Girl

A 6-month-old boy presents with a temperature of 38.9°C and barking cough of 3 days’ duration as well as a rash over his body for 1 day. On physical examination, his temperature is 37.5°C, respiratory rate is 28 breaths/min, and blood pressure is 87/52 mm Hg. He appears nontoxic and has a barking cough, injected conjunctiva with whitish discharge, dry lips, mild inspiratory stridor, a blanching erythematous maculopapular rash on his trunk and extremities, and small cervical lymph nodes. The rest of his physical findings are normal. His Hgb is 12.8 g/dL (128 g/L), WBC count is 11.7×103/mcL (11.7×109/L) with 75% neutrophils and 23% lymphocytes, and platelet count is 515×103/mcL (515×109/L). His stridor is considered to be due to viral croup, and he is treated with intramuscular (IM) dexamethasone and nebulized racemic epinephrine. A lateral neck radiograph reveals widening of the retropharyngeal space (Fig. 1), and he is started on clindamycin. CT scan of the neck reveals a right retropharyngeal abscess (Fig. 2). He continues to have high spiking fevers and experiences stridor at rest. He is started on IM dexamethasone every 6 hours, and his fever subsides the following day. Figure 1. Lateral neck radiograph showing widening of the retropharyngeal space. Figure 2. CT scan of the neck showing a right retropharyngeal abscess (arrow). On hospital day 6, the corticosteroids are stopped, but the fever returns the following day. Two days later, an erythematous maculopapular rash reappears, and the child’s lips are dry and cracked. On day 10, repeat CT scan shows that the retropharyngeal abscess has resolved. An additional imaging study reveals the cause of his symptoms. A 3-month-old previously healthy girl presents to the ED with a 1-day history of a blistering rash. Her parents noted an erythematous area on her occiput after …

Abstract A101: Dose-related suppression of rat oral carcinogenesis by the EGF receptor-tyrosine kinase inhibitor, gefitinib

Abstract Activation of the epidermal growth factor receptor (EGFR) stimulates signal transduction pathways that regulate cell proliferation and may be causally involved in carcinogenesis. Recent data suggest that EGFR expression is a predictive biomarker for the risk of oral cancer in humans, and that alterations in EGFR expression or action may be directly involved in oral carcinogenesis. Gefitinib (N-(3-chloro-4-fluoro-phenyl)-7-methoxy-6-(3-morpholin-4-ylpropoxy)-quinazolin-4-amine; ZD1839; Iressa) is a specific inhibitor of EGFR tyrosine kinase (EGFR-TK). The present study was performed to evaluate the activity of gefitinib as an inhibitor of oral cancer induction in rats. Squamous cell carcinomas of the tongue were induced in male F344 rats by drinking water administration of 4-nitroquinoline-1-oxide (NQO; 20 ppm for 10 weeks). After NQO administration was completed, rats were randomized into groups of 25 and received [a] unsupplemented basal diet only (dietary control); [b] basal diet + gefinitib (50 mg/kg diet); or [c] basal diet + gefinitib (100 mg/kg diet). All diets were fed continuously from week 10 until the end of the study at week 26. Dietary administration of gefinitib induced a dose-related inhibition of oral cancer induction (cancer incidences of 57% and 36% in low and high dose groups, respectively, versus 80% incidence in the dietary control group; p < 0.01), and prevented the body weight loss that is commonly seen in this model in animals with advanced oral cancer. While reducing the incidence of invasive oral cancers, gefinitib increased the incidence of squamous epithelial hyperplasia (35% and 40% in low and high dose groups, respectively, versus 16% in dietary controls); the increased incidence of oral epithelial hyperplasia suggests that gefinitib prevented the progression of hyperplastic lesions into invasive oral cancers. Gefinitib induced no evidence of systemic toxicity in any treated animal. PCR analysis demonstrated comparable levels of EGFR transcripts in oral cancers and site-matched phenotypically normal oral tissues harvested from age-matched animals treated with NQO. Thus, the utility of EGFR-TK as a target for oral cancer chemoprevention in this model is not clearly associated with differential expression of EGFR in neoplastic oral tissues. These data demonstrate that EGFR inhibitors may be useful for the prevention of oral cancer, and that overexpression of EGFR in these cancers is not essential for chemopreventive efficacy. (Supported by N01-CN-85163 and N01-CN-25113 from the NCI.) Citation Information: Cancer Prev Res 2010;3(12 Suppl):A101.

A double-blind, placebo-controlled trial of a topical treatment for chemotherapy-induced peripheral neuropathy: NCCTG trial N06CA.

Chemotherapy-induced peripheral neuropathy (CIPN) is a troublesome chronic symptom that has no proven pharmacologic treatment. The purpose of this double-blind randomized placebo-controlled trial was to evaluate a novel compounded topical gel for this problem. Patients with CIPN were randomized to baclofen 10mg, amitriptyline HCL 40mg, and ketamine 20mg in a pluronic lecithin organogel (BAK-PLO) versus placebo (PLO) to determine its effect on numbness, tingling, pain, and function. The primary endpoint was the baseline-adjusted sensory subscale of the EORTC QLQ-CIPN20, at 4weeks. Data in 208 patients reveal a trend for improvement that is greater in the BAK-PLO arm over placebo in both the sensory (p = 0.053) and motor subscales (p = 0.021). The greatest improvements were related to the symptoms of tingling, cramping, and shooting/burning pain in the hands as well as difficulty in holding a pen. There were no undesirable toxicities associated with the BAK-PLO and no evidence of systemic toxicity. Topical treatment with BAK-PLO appears to somewhat improve symptoms of CIPN. This topical gel was well tolerated, without evident systemic toxicity. Further research is needed with increased doses to better clarify the clinical role of this treatment in CIPN.

Inhibition of established subcutaneous murine tumour growth with topical Melaleuca alternifolia (tea tree) oil

Systemic toxicity coupled with long treatment regimes of approved topical chemotherapeutic agents such as imiquimod and 5-fluorouracil (5-FU) are limiting. There is now more focus on the potential use of topical terpene agents as skin cancer treatments. Here, we show for the first time that topical Melaleuca alternifolia (tea tree) oil (TTO), abundant in terpenes, has in vivo antitumour activity. Topical TTO formulations applied to immunocompetent tumour-bearing mice were assessed for antitumour efficacy by monitoring tumour growth and by histological analysis following treatment. Four, daily, topical treatments of 10% TTO/DMSO regressed subcutaneous AE17 mesotheliomas in mice for a period of 10 days and significantly retarded the growth of subcutaneous B16-F10 melanomas. The antitumour effect of topical 10% TTO/DMSO was accompanied by skin irritation similar to other topical chemotherapeutic agents, but unlike other approved topical agents, quickly and completely resolved. Furthermore, we show that topical 10% TTO/DMSO caused an influx of neutrophils and other immune effector cells in the treated area, with no evidence of systemic toxicity. TTO combined with an effective carrier significantly inhibited the growth of aggressive, subcutaneous, chemo-resistant tumours in immunocompetent mice. Taken together, these findings highlight the potential of topical TTO as an alternative topical antitumour treatment.

Local and Systemic Toxicity of Intraoral Submucosal Injections of Phentolamine Mesylate (OraVerse)

OraVerse, an injectable formulation of phentolamine mesylate (PM), was recently approved by the U.S. Food and Drug Administration (FDA) for reversal of anesthesia of the lip and tongue and associated functional deficits resulting from an intraoral submucosal injection of a local anesthetic containing a vasoconstrictor. Because PM had not been approved previously for submucosal administration, 2 Good Laboratory Practices (GLP) studies in dogs designed to investigate systemic toxicity and the local effects of single and repeated dosing of OraVerse on the inferior alveolar nerve and branches of the superior alveolar nerve and adjacent soft tissues after local administration were conducted. Systemic toxicity was measured by preinjection and postinjection clinical examinations, clinical chemistry, and gross and microscopic examinations of major organs after necropsy. No evidence of systemic toxicity was detected. Local nerve and adjacent tissue damage was assessed by conventional histopathology. Nerve degeneration was evident in 1 animal. Mild perineural inflammation adjacent to the inferior alveolar nerve and inflammatory exudates were observed in submucosal tissues in several animals. No changes were observed in the nerves at injection sites of dogs from any dose group that were considered directly related to the test articles. These data reveal that single and repeated intraoral administrations of OraVerse are well tolerated in beagle dogs.

Biodegradable β‐Tri‐Calciumphosphate/hydroxyethyl methacrylate enhanced three component bone adhesive demonstrates biocompatibility without evidence of systemic toxicity in a rabbit model

Bone gluing is an attractive surgical technique; however, its use in patients is hampered by a variety of side effects. Therefore, it was the aim of this ethically approved study to evaluate a novel biodegradable beta-Tri-Calciumphosphate (beta-TCP, Cerasorb)-enhanced bone adhesive regarding its toxicity and biocompatibility in a rabbit model. Fifty healthy New Zealand White rabbits were assigned in the study (n = 21) and sham-operated control group (n = 29). In the study group, a cylindrical part (4.6 x 10.0 mm) of the proximal tibia and distal femur was removed, reimplanted, and bone adhesive was applied. Blinded physical examination and sampling for hematology, clinical chemistry, and acute phase proteins (haptoglobin, C-reactive protein (CRP)) was performed before surgery and after 12, 24, 48, 72, 240, and 504 h. Significant findings of the physical examination included a slightly higher grading of warmth (p = 0.0019) and pain (p < 0.0001) of the wound 240 h after surgery in the study group. No significant differences between albumin, haptoglobin, CRP, and urea concentrations in both groups were evident, whereas the study group demonstrated significantly lower leukocyte count, total protein, and globulin concentrations (p < 0.0001). As expected, both groups showed a marked transient increase in muscle enzymes (Creatine Kinase and Aspartate Aminotransferase) following the surgery (p < 0.0001). Twelve to 24 h after surgery, a significant decrease in ionized calcium from 1.38 +/- 0.12 mmol/L to 1.06 +/- 0.13 mmol/L was noted in the study group (p < 0.0001). The results clearly indicated that the novel beta-TCP-enhanced bone adhesive showed good biocompatibility without significant evidence of acute or subacute local or systemic toxicity.

Derivation of an Inhalation Reference Concentration Based upon Olfactory Neuronal Loss in Male Rats following Subchronic Acetaldehyde Inhalation

Acetaldehyde inhalation induces neoplastic and nonneoplastic responses in the rodent nasal cavity. This experiment further characterizes the dose-response relationship for nasal pathology, nasal epithelial cell proliferation, and DNA–protein cross-link formation in F-344 rats exposed subchronically to acetaldehyde. Animals underwent whole-body exposure to 0, 50, 150, 500, or 1500 ppm acetaldehyde for 6 h/day, 5 days/wk for up to 65 exposure days. Respiratory tract histopathology was evaluated after 4, 9, 14, 30, and 65 exposure days. Acetaldehyde exposure was not associated with reduced body weight gain or other evidence of systemic toxicity. Histologic evaluation of the nasal cavity showed an increased incidence of olfactory neuronal loss (ONL) following acute to subchronic exposure to ≥ 150 ppm acetaldehyde and increased olfactory epithelial cell proliferation following exposure to 1500 ppm acetaldehyde. The severity of the ONL demonstrated dose-and temporal-dependent behaviors, with minimal effects noted at 150–500 ppm acetaldehyde and moderately severe lesions seen in the highest exposure group, with increased lesion severity and extent as the exposure duration increased. Acetaldehyde exposure was also associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. These responses were seen in animals exposed to ≥500 ppm acetaldehyde. Acetaldehyde exposure was not associated with increased DNA–protein cross-link formation in the respiratory or olfactory epithelium. A model of acetaldehyde pharmacokinetics in the nose was used to derive an inhalation reference concentration (RfC) of 0.4 ppm, based on the no-observed-adverse-effect level (NOAEL) of 50 ppm for the nasal pathology seen in this study.

Chronic exposure to low levels of aluminum alters cerebral cell signaling in response to acute MPTP administration

Two-month-old male B/6C3F1 mice were treated for 10 weeks with 100 microM aluminum lactate (Al) in drinking water. This dose of Al did not alter body weight, and there was no evidence of systemic toxicity. The degree of phosphorylation of several kinases which lead to transcription factor activation (reflecting the extent of their activation) was studied. The proportion of extracellular signal-regulated kinase (ERK) that was activated was depressed in cortex but not in the hippocampus following treatment but c-Jun N-terminal kinase (JNK), p38, IkappaB phosphorylation was unaltered in either tissue. Treatment of mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) alone produced no significant changes in the degree of activation of any transcription factor studied. When MPTP dosing had been preceded by extended exposure to low levels of Al in drinking water, ERK activation was profoundly depressed in cortex and hippocampus, whereas JNK in hippocampus and IkappaB in cortex were greatly elevated. These changes consequent to exposure to both Al and MPTP were accompanied by an increase in NF-kappaB in both regions, whereas AP-1 was elevated in the hippocampus alone. Neither agent alone modulated AP-1 or NF-kappaB. Thus a synergistic interaction occurred between the toxicants. This interaction tended to promote the functioning of a kinase largely associated with inflammation and to depress that of ERK, which is associated with maintenance of cell survival. It is concluded that exposure to levels of Al with no evident toxicity can worsen the response to an acute challenge with MPTP. Al treatment alone was able to increase striatal 3,4-dihydroxyphenylacetic acid levels, suggesting an elevation of the rate of dopamine turnover in the striatum. However, no interaction in alteration of monoamine levels was found between Al and MPTP.

Acute Toxicity Evaluation of Proliferol: A Dose-Escalating, Placebo-Controlled Study in Rats

Proliferol is an investigational new drug containing lidocaine hydrochloride 0.25%, dextrose 12.5%, glycerin 12.5%, and phenol 1.0% in aqueous solution. Despite extensive human experience with similar drugs administered by intraligamentous injection for chronic musculoskeletal disorders, little is known concerning preclinical toxicity. The purpose of this study was to assess the acute toxicity of intramuscular Proliferol in 96 (48 male, 48 female) Charles River strain rats, which were randomly assigned to low- (1x), medium- (5x), or high- (10x) dose Proliferol (derived from a human dose of 20 ml on a volume per bodyweight basis), or high-dose saline placebo. Observations included clinical observations, biochemistry, hematology, urinalysis, and full histopathology after 24 h or 14 days. There were no signs of ill health or reaction to treatment, and gait and body temperature were within normal limits. Biochemistry findings at 24 h included elevated aspartate aminotransferase, alanine aminotransferase, and haptoglobin; at 14 days all values were within normal ranges. Urinalysis findings at 24 h included increased urobilinogen and blood in all dose groups compared with placebo. Urine concentrations of phenol and lidocaine were greatest at 2 h and absent at 24 h. Histopathology findings included localized acute inflammatory soft tissue changes at the injection sites at 24 h and skeletal muscle regeneration at 14 days, which were consistent with the anticipated mechanism of action of Proliferol. There was no evidence of systemic toxicity from intramuscular injection of Proliferol in rats at up to 10x the human dose.

Folate Receptor–Specific Antitumor Activity of EC131, a Folate-Maytansinoid Conjugate

EC131, a new folate receptor (FR)-targeted drug conjugate, was prepared by covalently attaching the vitamin folic acid (FA) to a potent microtubule-inhibiting agent, maytansinoid DM1, via an intramolecular disulfide bond. When tested on cells in culture, EC131 was found to retain high affinity for FR-positive cells and to provide FR-specific cytotoxicity with an IC(50) in the low nanomolar range. The activity of EC131 was completely blocked in the presence of an excess of free FA, and no activity was detected against FR-negative cells. When evaluated against s.c. FR-positive M109 tumors in BALB/c mice, EC131 showed marked antitumor efficacy. Furthermore, this therapeutic effect occurred in the apparent absence of weight loss or noticeable organ tissue degeneration. In contrast, no significant antitumor activity was observed in EC131-treated animals that were codosed with an excess of FA, thus demonstrating the targeted specificity of the in vivo activity. EC131 also showed marked antitumor activity against FR-positive human KB tumors, but not against FR-negative A549 tumors, in nude mice with no evidence of systemic toxicity during or after the therapy. In contrast, therapy with the free maytansinoid drug (in the form of DM1-S-Me) proved not to be effective against the KB model when administered at its maximum tolerated dose (MTD). Taken together, these results indicate that EC131 is a highly potent agent capable of producing therapeutic benefit in murine tumor models at sub-MTD levels.

Honokiol, a natural plant product, inhibits the bone metastatic growth of human prostate cancer cells

Honokiol, a soluble nontoxic natural product derived from Magnolia spp., has been shown to induce apoptosis in malignant cells. The effect of honokiol and the combined therapy with docetaxel on prostate cancer (PCa) growth and bone metastasis was investigated in experimental models. The in vitro proapoptotic effects of honokiol on human androgen-dependent and -independent PCa, bone marrow, bone marrow-derived endothelial, and prostate stroma cells were investigated. Honokiol-induced activation of caspases was evaluated by Western blot and FACS analysis. To confirm the cytotoxicity of honokiol, mice bone was inoculated in vivo with androgen-independent PCa, C4-2 cells and the effects of honokiol and/or docetaxel on PCa growth in bone were evaluated. Daily honokiol (100 mg/kg) and/or weekly docetaxel (5 mg/kg) were injected intraperitoneally for 6 weeks. PCa growth in mouse bone was evaluated by radiography, serum prostate-specific antigen (PSA) and tissue immunohistochemistry. Honokiol induced apoptosis in all cell lines tested. In PCa cells honokiol induced apoptosis via the activation of caspases 3, 8, and 9 and the cleavage of poly-adenosine diphosphate ribose polymerase in a dose- and time-dependent manner. Honokiol was shown to inhibit the growth and depress serum PSA in mice harboring C4-2 xenografts in the skeleton and the combination with docetaxel showed additive effects that inhibited further growth without evidence of systemic toxicity. Immunohistochemical staining confirmed honokiol exhibited growth-inhibitory, apoptotic, and antiangiogenic effects on PCa xenografts. The combination of honokiol and low-dose docetaxel may be used to improve patient outcome in androgen-independent prostate cancer with bone metastasis.

Phase II study of capecitabine (X) plus reirradiation in patients (pts) with recurrent squamous cell carcinoma of the head and neck (SCCHN)

15504 Background: X has shown substantial activity in SCCHN [Pivot et al. 2004] and is replacing 5-FU as the backbone of chemotherapy in a wide range of solid tumors, particularly colorectal cancer. In addition, X has a unique survival benefit in breast cancer. There is substantial data to support using X in chemoradiation [Dunst et al. 2004]. We evaluated the therapeutic impact and safety profile of X plus reirradiation in SCCHN. Methods: Pts with locally advanced unresectable SCCHN who had prior radiotherapy (RT, with or without chemotherapy) received X 450 mg/m2 twice daily, 7 days a week. RT was delivered as a standard fractionated regimen (2 Gy/day, 5 fractions/week) up to a total dose of 50–70 Gy. The cumulative (life-time) dose within overlapping fields was not to exceed 120–130 Gy. Results: Currently, 20 male pts have completed treatment. Baseline characteristics were: median age 57 (42–72), ECOG PS 0/1 5/15. Six pts had previous chemoradiation followed by radical resection; 4 had surgery and postoperative RT; 10 had concomitant chemoradiation (accelerated and hyperfractionated). Twelve pts experienced locoregional recurrences, 4 developed secondary primaries, and 4 had a regional lymph node relapse. The median time since prior radiation therapy was 16 (8–244) months. Efficacy (as evaluated by WHO criteria): 7 pts (35%) had a complete (2) or partial (5) response; stable disease was observed in 11 pts, and tumor progression immediately after therapy was observed in 2 pts. Median duration of local control and median survival will be presented at the meeting. The most frequently observed toxicity was mucositis, which was grade 3 in only 2 pts; grade 1 or 2 skin reaction was seen in 9 pts. There was no evidence of systemic toxicity or myelosuppression, probably due to the very low dose of X. RT was completed without delay in all pts, and X was interrupted prematurely in 2 pts due to grade 3 mucositis. Conclusions: Our preliminary data suggest that X chemoradiation is a well-tolerated and effective treatment modality for previously irradiated pts with SCCHN. Based on available data, a higher dose of X should be feasible and potentially more effective. Earlier use of X in SCCHN could also be evaluated. [Table: see text]

CLinical experience acquired with the efalizumab (Raptiva®) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from a phase III international randomized, placebo-controlled trial

Efalizumab (anti-CD11a), a humanized monoclonal antibody, blocks multiple T-cell-dependent functions implicated in the pathogenesis of psoriasis, including T-cell activation, migration to the skin, reactivation in psoriatic skin and interactions with keratinocytes. This multinational, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the safety and efficacy of subcutaneous efalizumab 1.0 mg kg-1 once weekly for 12 weeks compared with placebo in a population that included high-need patients, defined as those for whom at least two systemic therapies were unsuitable because of lack of efficacy, intolerance or contraindication. Patients with moderate-to-severe plaque psoriasis [involvement of >or=10% of total body surface area and Psoriasis Area and Severity Index (PASI)>or=12.0 at screening] were randomized in a 2:1 ratio to receive efalizumab or placebo. The primary efficacy endpoint was the proportion of patients achieving >or=75% PASI improvement (PASI-75 response) at week 12 in the intention-to-treat population; secondary endpoints included changes in PASI, static Physician's Global Assessment, Physician's Global Assessment of change from baseline and percentage of body surface area affected. Results We enrolled 793 patients (529 received efalizumab and 264 placebo), including 526 high-need patients (342 received efalizumab and 184 placebo). Week 12 PASI-75 rates were 29.5% for efalizumab compared with 2.7% for placebo among high-need patients (P<0.0001) and 31.4% for efalizumab compared with 4.2% for placebo in the full study population (P<0.0001). for all secondary efficacy endpoints showed superiority of efalizumab over placebo in both the high-need and the full populations. Efalizumab demonstrated a favourable safety profile, without evidence of systemic toxicity, in both the high-need group and the overall study population. The efficacy and safety of efalizumab therapy were comparable between high-need patients and the more general moderate-to-severe psoriasis patient population. In view of its demonstrated efficacy and safety profile, efalizumab represents a valuable option for the treatment of adult patients with moderate-to-severe plaque psoriasis, including high-need patients.

Ductal Access for Prevention and Therapy of Mammary Tumors

In cancer patients and in those at high risk, systemic exposure to agents for therapy or prevention is accompanied by undesirable side effects. We hypothesized that it is possible to prevent and treat breast cancer by introducing anticancer agents into the mammary ductal network. Here, we show the efficacy of intraductally administered anticancer agents 4-hydroxytamoxifen and pegylated liposomal doxorubicin (PLD) in the prevention and treatment of breast cancer using the rat N-methyl-N'-nitrosourea-induced and spontaneous HER-2/neu transgenic mouse (neu-N) models of breast cancer. Intraductal administration of PLD to neu-N mice caused regression of established tumors and prevented tumor development more effectively than i.v. injection (P < 0.0001). Intraductal administration resulted in lower circulating levels of PLD compared with i.v. administration, with no evidence of systemic toxicity or long-term histopathologic changes in the mammary gland. Compared with systemic administration, intraductal injection provides direct access to breast lesions with higher local and lower systemic drug exposure. These studies suggest that this approach has potential for application to prevention and neoadjuvant therapy of early breast cancer.

Subacute Inhalation Exposure of Rats to 1,6-Hexamethylene Diisocyanate With Recovery Period

In this subacute inhalation toxicity study of 1,6-hexamethylene diisocyanate (HDI), groups of 10 male and 10 female Sprague-Dawley rats were exposed to 0, 0.005, 0.0175, or 0.150 ppm HDI vapor, 5 h/ /day, 5 days/ /wk for 15 exposure days and included animals sacrificed 2 wk postexposure. The purpose was to characterize the HDI-induced effects and their reversibility, and to determine a no-observed-adverse-effect level (NOAEL). No compound-related effects were found for body weights, clinical chemistry, urinalysis, hematology, and organ weights. Thus, no evidence of systemic toxicity was found in this study. The exposure-related findings were restricted to the portal of entry, the respiratory tract. Transient signs of sensory irritation were observed after the daily exposure periods, but the principal findings were the histopathologic changes of the nasal epithelium. Generally, an anterior to posterior gradient of incidence and severity was found, and the changes were characterized as acanthosis, erosion, hyperkeratosis, epithelial cell hyperplasia, chronic active inflammation, squamous metaplasia, ulceration, transitional epithelial cell degeneration, goblet-cell hyperplasia, and degeneration of the olfactory epithelium. Varying degrees of concordance between exposure concentration and incidence and/or severity of the histopathologic changes were found. During a 2-wk recovery period, a tendency toward recovery was evident for tissue changes in the nasal cavity. A NOAEL of 0.0175 ppm HDI was determined.

Local intracerebral administration of Paclitaxel with the paclimer delivery system: toxicity study in a canine model.

Paclitaxel, a microtubule binding agent with potent anti-glioma activity in vitro, exhibits poor penetrance to the CNS when delivered systemically. To minimize toxicity and reach therapeutic concentrations in the CNS, paclitaxel was previously incorporated into biodegradable microspheres (Paclimer), and the efficacy of Paclimer was determined in a rat model of malignant glioma. In this study we report the safety of intracranial Paclimer in a canine dose escalation toxicity study to prepare its translation into clinical scenarios. Twelve normal beagle dogs underwent a right parieto-occipital craniectomy and were randomized to receive either Paclimer at 2-mg/kg (n=5), empty microspheres at 2-mg/kg (n=1), Paclimer at 20-mg/kg (n=5), or empty microspheres at 20-mg/kg (n=1). Post-operatively, dogs were observed daily for signs of neurotoxicity. Complete blood counts and plasma levels of paclitaxel were obtained weekly. CSF levels and MRI scans were obtained on days 14-120. Paclitaxel concentrations were quantified by LC-MS. Animals treated with 20-mg/kg Paclimer had minimal paclitaxel levels in plasma (range 0-7.84 ng/ml) and CSF (range 0-1.16 ng/ml). Animals treated with 2 mg/kg Paclimer had undetectable levels of paclitaxel in plasma, CSF was not obtained to minimize animal suffering. All animals exhibited normal behavior and weight gain, and were alive post-operatively through the last day of the study (day 60-120) without signs of neurological toxicity. There was no evidence of systemic toxicity or myelosuppression. MR imaging was comparable between Paclimer animals and controls. Adverse effects included wound infections and a brain abscess, all of which responded to antibiotic therapy, and one ventriculomegaly due to communicating hydrocephalus. Paclimer-based delivery of paclitaxel is safe for intraparenchymal delivery at the tested doses in normal dogs.