Association of clinical factors and recent anticancer therapy with COVID-19 severity among patients with cancer: a report from the COVID-19 and Cancer Consortium.

BACKGROUND: Patients with cancer may be at high risk of adverse outcomes from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We analyzed a cohort of patients with cancer and coronavirus 2019 (COVID-19) reported to the COVID-19 and Cancer Consortium (CCC19) to identify prognostic clinical factors, including laboratory measurements and anticancer therapies. PATIENTS AND METHODS: Patients with active or historical cancer and a laboratory-confirmed SARS-CoV-2 diagnosis recorded between 17 March and 18 November 2020 were included. The primary outcome was COVID-19 severity measured on an ordinal scale (uncomplicated, hospitalized, admitted to intensive care unit, mechanically ventilated, died within 30 days). Multivariable regression models included demographics, cancer status, anticancer therapy and timing, COVID-19-directed therapies, and laboratory measurements (among hospitalized patients). RESULTS: A total of 4966 patients were included (median age 66 years, 51% female, 50% non-Hispanic white); 2872 (58%) were hospitalized and 695 (14%) died; 61% had cancer that was present, diagnosed, or treated within the year prior to COVID-19 diagnosis. Older age, male sex, obesity, cardiovascular and pulmonary comorbidities, renal disease, diabetes mellitus, non-Hispanic black race, Hispanic ethnicity, worse Eastern Cooperative Oncology Group performance status, recent cytotoxic chemotherapy, and hematologic malignancy were associated with higher COVID-19 severity. Among hospitalized patients, low or high absolute lymphocyte count; high absolute neutrophil count; low platelet count; abnormal creatinine; troponin; lactate dehydrogenase; and C-reactive protein were associated with higher COVID-19 severity. Patients diagnosed early in the COVID-19 pandemic (January-April 2020) had worse outcomes than those diagnosed later. Specific anticancer therapies (e.g. R-CHOP, platinum combined with etoposide, and DNA methyltransferase inhibitors) were associated with high 30-day all-cause mortality. CONCLUSIONS: Clinical factors (e.g. older age, hematological malignancy, recent chemotherapy) and laboratory measurements were associated with poor outcomes among patients with cancer and COVID-19. Although further studies are needed, caution may be required in utilizing particular anticancer therapies. CLINICAL TRIAL IDENTIFIER: NCT04354701.

A novel approach for establishing fitness standards for occupational task performance.

PURPOSE: To identify strength and performance thresholds below which task performance is impaired. METHODS: A new weighted suit system was used to manipulate strength-to-body-weight ratio during the performance of simulated space explorations tasks. Statistical models were used to evaluate various measures of muscle strength and performance on their ability to predict the probability that subjects could complete the tasks in an acceptable amount of time. Thresholds were defined as the point of greatest change in probability per change in the predictor variable. For each task, median time was used to define the boundary between "acceptable" and "unacceptable" completion times. RESULTS: Fitness thresholds for four space explorations tasks were identified using 23 physiological input variables. Area under receiver operator characteristic curves varied from a low of 0.68 to a high of 0.92. CONCLUSION: An experimental analog for altering strength-to-body weight combined with a probability-based statistical model for success was suitable for identifying thresholds for task performance below which tasks could either not be completed or time to completion was unacceptably high. These results provide data for strength recommendations for exploration mission ambulatory task performance. Furthermore, the approach can be used to identify thresholds for other areas where occupationally relevant tasks vary considerably.

Isometric Midthigh Pull Reliability and Relationship to Deadlift One Repetition Maximum.

De Witt, JK, English, KL, Crowell, JB, Kalogera, KL, Guilliams, ME, Nieschwitz, BE, Hanson, AM, and Ploutz-Snyder, LL. Isometric midthigh pull reliability and relationship to deadlift one repetition maximum. J Strength Cond Res 32(2): 528-533, 2018-The purpose of this investigation was to examine the reliability of the isometric midthigh pull (IMTP) and the relationship between IMTP peak force and deadlift 1 repetition maximum (1RM). Nine subjects (5 men and 4 women; 40.6 ± 8.0 years; 1.72 ± 0.10 m; 75.6 ± 13.4 kg) participated in this study. Isometric midthigh pull and deadlift 1RM were both performed during 2 testing sessions. For IMTP, peak force and peak rate of force development (RFD) were determined, in addition to RFD at 30 ms, 50 ms, 90 ms, 150 ms, 200 ms, and 250 ms after initiation of the pull. Intraclass correlation coefficients (ICCs) were calculated to evaluate the reliability of IMTP measures. Pearson product-moment correlations and linear regression were used to determine associations between IMTP and deadlift 1RM. Isometric midthigh pull peak force was reproducible both within (ICC = 0.98 and 0.97) and between sessions (ICC = 0.89) and significantly correlated with deadlift 1RM (r = 0.88, p ≤ 0.05), but intermediate force outputs and RFD were not. Lack of associations between RFD and deadlift 1RM indicate that the ability to create explosive force may be independent of the ability to create maximal force. The strong relationship between IMTP peak force and deadlift 1RM was present regardless of which IMTP repetition across the 2 sessions was examined. Peak force generated during IMTP is a reliable method to assess full body maximal strength. A single IMTP repetition, provided adequate familiarization and warm-up, correlates strongly with deadlift 1RM. Practitioners can use the IMTP test as a method to estimate maximal deadlift strength in a quick and potentially less provocative manner than traditional 1RM testing.

Posttraumatic stress disorder, alone or additively with early life adversity, is associated with obesity and cardiometabolic risk.

BACKGROUND AND AIMS: There is some evidence that posttraumatic stress disorder (PTSD) and early life adversity may influence metabolic outcomes such as obesity, diabetes, and cardiovascular disease. However, whether and how these interact is not clear. METHODS: We analyzed data from a cross-sectional and longitudinal study to determine how PTSD severity influences obesity, insulin sensitivity, and key measures and biomarkers of cardiovascular risk. We then looked at how PTSD and early life adversity may interact to impact these same outcomes. RESULTS: PTSD severity is associated with increasing risk of obesity, diabetes, and cardiovascular disease, with higher symptoms correlating with higher values of BMI, leptin, fibrinogen, and blood pressure, and lower values of insulin sensitivity. PTSD and early life adversity have an additive effect on these metabolic outcomes. The longitudinal study confirmed findings from the cross sectional study and showed that fat mass, leptin, CRP, sICAM-1, and sTNFRII were significantly increased with higher PTSD severity during a 2.5 year follow-up period. CONCLUSIONS: Individuals with early life adversity and PTSD are at high risk and should be monitored carefully for obesity, insulin resistance, and cardiometabolic risk.

Sweat Production During Continuous and Interval Aerobic Exercise.

INTRODUCTION:Aerobic exercise within the habitable volume of small spacecraft needed for space exploration beyond low Earth orbit is expected to challenge the capacity of environmental control systems. Moisture control is a primary concern. Crewmembers will contribute moisture to the cabin environment in the form of sweat while exercising. The effects of continuous aerobic exercise for improving and maintaining aerobic capacity is well characterized. Likewise, evidence suggests that high intensity interval exercise for shorter durations is also effective in building and maintaining aerobic capacity.METHODS: On separate days, measures of sweat and respiratory responses were made for continuous (30 min of steady state exercise at ∼75% of aerobic capacity) and two interval (4 × 4 min, 8 × 30 s) exercise protocols.RESULTS: We observed that the 4-min and 30-s interval protocols produce 16% and 66% less metabolic water loss vs. the continuous exercise protocol, respectively. These responses were highly correlated with the amount of work performed (R² = 0.81) and the amount of energy expenditure (R² = 0.83) during exercise.DISCUSSION: These results suggest that interval exercise may be a useful alternative to continuous aerobic exercise when metabolic water production is an environmental concern. The results may inform the choices of aerobic exercise countermeasure protocols for use in deep space exploration.Ryder JW, Crowell JB, Song HJ, Ewert M. Sweat production during continuous and interval aerobic exercise. Aerosp Med Hum Perform. 2023; 94(8):623-628.

Distribution of lymphocytes identified by surface markers in murine strains with systemic lupus erythematosus-like syndromes.

The frequencies and absolute numbers of B and T cells in the lymphoid organs of five murine strains (NZB, (NZB X NZW)F1, BXSB, MRL/l, and MRL/n) with SLE-like syndromes were examined. We assessed the frequencies of cells bearing surface Ig, C3d and IgG Fc receptors, and theta-antigen. The sequential expression of Ig isotopes on developing B cells and the Ig isotypes expressed on adult B cells were ascertained. In addition, the Ly subsets and the expression of Ia antigens coded for by the I-J subregion of the mouse H-2 complex were examined. Compared to normal, older mice, New Zealand mice had low frequencies and absolute numbers of B cells, BXSB mice had a moderate B-cell proliferation, and MRL/l mice had normal absolute numbers of B cells but a reduced frequency concomitant with a massive T-cell proliferation. Old New Zealand mice and BXSB mice had reduced frequencies and absolute numbers of T cells compared to old controls. The developmental Ig-isotype diversity during the 1st wk of age was similar in normal mice and those with autoimmune manifestations. Mature B cells were present in lymphoid organs of New Zealand mice and BXSB mice as evidenced by the high frequency of C3d receptor-bearing cells and Ig-isotype expression (high ratio of IgM- to IgD-bearing cells) in adult spleen cells. Numbers of IgG Fc receptor-bearing cells were reduced in autoimmune mice with advanced age and disease. The proliferating T cells in MRL/l mice were found to be theta-antigen positive but Ly null. These theta+-, Ly null cells may have arisen from Ly123+ T cells. MRL/l and BXSB mice seemed normal in their content of T cells bearing Ia antigens coded for by the I-J subregion of H-2. Overall, mice with autoimmune manifestations appear to express perturbations in T and B cells with development of disease, and their patterns of change vary from one strain to another.

Movement directions in late paleozoic glacial rocks of the horlick and pensacola mountains, antarctica.

Striae and associated structures beneath and within the Buckeye Tillite in the Ohio Range of the Horlick Mountains show that Permian(?) glaciers moved toward the west-southwest. Striae in the Wisconsin Range of the Horlicks display similar orientation, but the sense of movement could not be determined. Paleoglaciers in the Neptune Range and the Cordiner Peaks of the Pensacola Mountains moved toward the south-southwest with some dispersion. Paleocurrents flowed parallel to ice motion in the Ohio Range and in the Pensacolas, but they also flowed toward the north-northeast in the Pensacolas.

Subchronic oral toxicity studies of Se-methylselenocysteine, an organoselenium compound for breast cancer prevention.

Se-methylselenocysteine (MSC) is an organoselenium compound being developed for breast cancer chemoprevention. To characterize MSC toxicity, CD rats received daily gavage doses of 0, 0.5, 1.0, or 2.0 mg/kg/day (0, 3, 6, or 12 mg/m(2)/day), and beagle dogs received daily gavage doses of 0, 0.15, 0.3, or 0.6 mg/kg/day (0, 3, 6, or 12 mg/m(2)/day) for 28 days. In rats, MSC induced dose-related hepatomegaly in both sexes; mild anemia, thrombocytopenia, and elevated liver enzymes were observed in high dose females only. Microscopic pathology included hepatocellular degeneration (high dose males, all doses in females); arrested spermatogenesis (high dose males); and atrophy of corpora lutea (middle and high dose females). In dogs, MSC induced mild anemia in middle and high dose males, and in high dose females. Toxicologically significant microscopic lesions in dogs were seen only in the liver (peliosis and vacuolar degeneration in high dose males, midzonal necrosis in males in all dose groups). Based on liver pathology seen in female rats in all dose groups, the no observed adverse effect level (NOAEL) for MSC in rats is <0.5mg/kg/day. Based on alterations in hematology parameters and liver morphology in male dogs in all dose groups, the NOAEL for MSC in dogs is <0.15 mg/kg/day.

Visual self-motion perception during head turns.

Extra-retinal information is critical in the interpretation of visual input during self-motion. Turning our eyes and head to track objects displaces the retinal image but does not affect our ability to navigate because we use extra-retinal information to compensate for these displacements. We showed observers animated displays depicting their forward motion through a scene. They perceived the simulated self-motion accurately while smoothly shifting the gaze by turning the head, but not when the same gaze shift was simulated in the display; this indicates that the visual system also uses extra-retinal information during head turns. Additional experiments compared self-motion judgments during active and passive head turns, passive rotations of the body and rotations of the body with head fixed in space. We found that accurate perception during active head turns is mediated by contributions from three extra-retinal cues: vestibular canal stimulation, neck proprioception and an efference copy of the motor command to turn the head.

Preliminary evidence for neural responsiveness to infants in mothers with schizophrenia and the implications for healthy parenting.

Schizophrenia is a severe mental illness that may significantly affect maternal sensitive behaviour. Neural correlates of maternal behaviour represent a potentially valuable means of differentiating objectively between healthy mothers expressing variations in maternal sensitivity. As mothers with schizophrenia (MWS) show deficits in behavioural responses to infants compared to healthy mothers, we explored whether maternal brain responses to infant stimuli would be significantly reduced in MWS. We also examined whether differences in maternal behaviour between healthy and ill mothers (during play interactions with own infant) were associated with differences in brain activation to infant stimuli. We found no evidence of differential 'maternal brain' responses or 'maternal behavioural' responses in 11 new MWS compared to 20 healthy new mums; neither were neural responses to infants linked to behavioural or cognitive aspects of the mother's relationship with her infant in MWS. These preliminary findings suggest maternal sensitivity differences between MWS and healthy mothers, suggested in previous studies, may be reversible in stable treated MWS.

Oncogenicity evaluation of resveratrol in p53(+/-) (p53 knockout) mice.

A six-month study was conducted in p53(+/-) mice to evaluate the possible oncogenicity of resveratrol (3,5,4'-trihydroxy-trans-stilbene), a cancer chemopreventive agent present in grapes and other foods. p53(+/-) mice (25/sex/group) received daily gavage exposure to vehicle only (negative control), resveratrol doses of 1000, 2000, or 4000 mg/kg/day, or p-cresidine (400 mg/kg/day; positive control). No mortality was seen in mice receiving the low dose of resveratrol. However, the mid and high doses induced mortality associated with impaction of the test article in the gastrointestinal tract. Resveratrol had no effect on body weight, food consumption, or clinical signs in surviving mice in any dose group, but induced dose-related increases in liver weight and serum cholesterol in both sexes. Mild anemia was seen in male mice at the high dose only; hematologic effects were not seen in females. Histopathology identified the kidney (hydronephrosis) and urinary bladder (epithelial hyperplasia) as target tissues for resveratrol toxicity. The incidences of both benign and malignant tumors in mice exposed to resveratrol were comparable to those in vehicle controls. By contrast, the positive control article, p-cresidine, induced urinary bladder cancer in both sexes. When administered to p53(+/-) mice at its maximum tolerated dose, resveratrol demonstrates no evidence of oncogenicity.

Virtual street-crossing performance in persons with multiple sclerosis: Feasibility and task performance characteristics.

OBJECTIVES: Multiple sclerosis (MS) is a neurological disease that commonly results in physical and cognitive dysfunction. Accordingly, MS might impact the ability to safely cross the street. The purpose of this study was to examine the feasibility of a simulated street-crossing task in persons with MS and to determine differences in street-crossing performance between persons with MS and non-MS controls. METHODS: 26 participants with MS (median Expanded Disability Status Scale [EDSS] score = 3.5) and 19 controls completed 40 trials of a virtual street-crossing task. There were 2 crossing conditions (i.e., no distraction and phone conversation), and participants performed 20 trials per condition. Participants were instructed that the goal of the task was to cross the street successfully (i.e., without being hit be a vehicle). The primary outcome was task feasibility, assessed as completion and adverse events. Secondary outcomes were measures of street-crossing performance. RESULTS: Overall, the simulated street-crossing task was feasible (i.e., 90% completion, no adverse events) in participants with MS. Participants with MS waited longer and were less attentive to traffic before entering the street compared with controls (all P < .05). Participants with MS also took longer to cross the street and were closer to oncoming vehicles when exiting the street compared to controls (all P < .05). When distracted, all participants took longer to initiate crossing, took longer to cross the street, and made more head turns while crossing (all P < .05). There were no significant group by condition interaction effects (all P > .05). CONCLUSIONS: A virtual street-crossing task is feasible for studying street-crossing behavior in persons with mild MS and most individuals with moderate MS. Virtual street-crossing performance is impaired in persons with MS compared to controls; however, persons with MS do not appear to be more vulnerable to a distracting condition. The virtual reality environment presents a safe and useful setting for understanding pedestrian behavior in persons with MS.

Suppression of human colorectal mucosal prostaglandins: determining the lowest effective aspirin dose.

BACKGROUND: A variety of studies have supported the finding that regular intake of aspirin (acetylsalicylic acid) or nonsteroidal anti-inflammatory agents can affect colorectal cancer carcinogenesis. These agents inhibit the synthesis of prostaglandins. High levels of prostaglandins are observed in colon cancer tissues. PURPOSE: Experiments were planned to determine the lowest dose of aspirin that can markedly suppress the levels of mucosal prostaglandins E2 and F(2alpha) in colorectal mucosa and to determine whether a relationship exists between these levels and plasma levels of both acetylsalicylic acid and its metabolite, salicylic acid. METHODS: Healthy men and women aged 18 years or older participated in the study. The participants took a single, daily dose of aspirin (40.5, 81, 162, 324, or 648 mg) or a placebo for 14 days. Colorectal biopsy specimens were taken at baseline, 24 hours after the first dose of aspirin, and 24-30 hours and 72-78 hours after the last, i.e., fourteenth, daily dose of aspirin. The biopsy specimens were assayed for prostaglandins E2 and F(2alpha) by use of a competitive enzyme immunoassay. Plasma concentrations of acetylsalicylic acid and salicylic acid were determined by use of high-performance liquid chromatography. All P values are two-sided. RESULTS: A total of 65 subjects (10 receiving placebo, groups of 10 each receiving 40.5, 81, 162, or 324 mg of aspirin, and a group of 15 receiving 648 mg of aspirin) completed the protocol. One subject reported unacceptable drug-induced toxic effects and did not complete the protocol; other subjects reported acceptable side effects. The lowest dose to significantly suppress colorectal mucosal prostaglandin E2 concentrations from baseline at 24 hours after the first dose (by 22.6%; P = .002) and at 24-30 hours after the last dose (by 14.2%; P = .021) was 162 mg. At 72-78 hours after the last dose, there was significant suppression for subjects receiving 81 mg (by 23.7%; P = .008). The lowest dose to significantly suppress colorectal mucosal prostaglandin F(2alpha) concentrations from baseline at 24 hours after the first dose (by 18.3%; P = .032) was 324 mg. The lowest dose causing a marked reduction in the level of prostaglandin F(2alpha) at 24-30 hours (by 15.1%; P = .003) and 72-78 hours (by 23.0%; P = .0002) after the last dose was 40.5 mg. No detectable amounts of acetylsalicylic acid or salicylic acid were present in the plasma at any of the biopsy time points. CONCLUSIONS: The lowest doses of aspirin taken daily for 14 days to significantly suppress concentrations of colorectal mucosal prostaglandins E2 and F(2alpha) were 81 and 40.5 mg, respectively. The suppression occurred without detectable amounts of aspirin or salicylic acid in the plasma at the time points studied. On the basis of these observations, we recommend a single, daily dose of 81 mg of aspirin in future studies of this drug as a chemopreventive agent for colorectal cancer.

Progress in cancer chemoprevention: perspectives on agent selection and short-term clinical intervention trials.

The basic cancer-related chemical and biological sciences, pathology, and epidemiology have contributed to the understanding that antimutagenesis and antiproliferation are the important general mechanisms of chemoprevention and to the development of antimutagenic and anti-proliferative agents as potential chemopreventive drugs. These disciplines have also provided the biochemical and histopathological bases for identifying intermediate biomarkers that can be used as surrogate end points for cancer incidence in clinical chemoprevention trials and for selecting cohorts for these trials. Particularly important as histological biomarkers of cancer are the cytonuclear morphological and densitometric changes that define intraepithelial neoplasia (IEN). IEN changes are on the causal pathway to cancer. They may serve as target lesions in Phase II chemoprevention trials and as standards against which other earlier cellular and molecular biomarkers can be evaluated. Strategies for the clinical evaluation of chemopreventive agents have been defined for seven targets--colorectal, prostate, lung, breast, bladder, oral, and cervical cancers. Cohorts have been identified for short-term Phase II trials that investigate the effects of chemopreventive agents on IEN and on earlier biomarkers. Patients with adenomas serve as a cohort for trials in colon. One cohort for Phase II trials in prostate is patients with early stage cancers scheduled for prostatectomy; another is patients with prostatic intraepithelial neoplasia (without prostatic carcinoma). Patients treated for lung cancer are at high risk for bronchial dysplasia and second cancers; such patients are a cohort for Phase II trials in lung cancer. Presurgical breast cancer patients and patients with ductal or lobular carcinoma in situ are cohorts for studies in breast. Patients with superficial bladder cancers (Ta/T1 with or without carcinoma in situ) are cohorts for studies of chemoprevention in bladder, and patients with dysplastic oral leukoplakia are evaluated for chemoprevention of oral cancers. Cervical intraepithelial neoplasia is a prototype IEN, and patients with cervical intraepithelial neoplasia are a cohort for studies of cervical cancer.

Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E.

Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. Its principal active components include epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin (EC), and epicatechin gallate, of which EGCG is the most abundant and possesses the most potent antioxidative activity. We performed a Phase I pharmacokinetic study to determine the systemic availability of green tea catechins after single oral dose administration of EGCG and Polyphenon E (decaffeinated green tea catechin mixture). Twenty healthy subjects (five subjects/dose level) were randomly assigned to one of the dose levels (200, 400, 600, and 800 mg based on EGCG content). All subjects were randomly crossed-over to receive the two catechin formulations at the same dose level. Blood and urine samples were collected for up to 24 h after oral administration of the study medication. Tea catechin concentrations in plasma and urine samples were determined using high-performance liquid chromatography with the coulometric electrode array detection system. After EGCG versus Polyphenon E administration, the mean area under the plasma concentration-time curves (AUC) of unchanged EGCG were 22.5 versus 21.9, 35.4 versus 52.2, 101.9 versus 79.7, and 167.1 versus 161.4 min x microg/ml at the 200-, 400-, 600-, and 800-mg dose levels, respectively. EGC and EC were not detected in plasma after EGCG administration and were present at low/undetectable levels after Polyphenon E administration. High concentrations of EGC and EC glucuronide/sulfate conjugates were found in plasma and urine samples after Polyphenon E administration. There were no significant differences in the pharmacokinetic characteristics of EGCG between the two study medications. The AUC and maximum plasma concentration (Cmax) of EGCG after the 800-mg dose of EGCG were found to be significantly higher than those after the 200- and 400-mg dose. The AUC and Cmax of EGCG after the 800-mg dose of Polyphenon E were significantly higher than those after the three lower doses. We conclude that the two catechin formulations resulted in similar plasma EGCG levels. EGC and EC were present in the body after the Polyphenon E administration; however, they were present predominantly in conjugated forms. The systemic availability of EGCG increased at higher doses, possibly due to saturable presystemic elimination of orally administered green tea polyphenols.

Oltipraz concentrations in plasma, buccal mucosa cells, and lipids: pharmacological studies.

Oltipraz is considered one of the most potent cancer chemoprevention agents, as shown in preclinical studies. Its pharmacological effects in humans have been associated with unusual toxicity affecting the fingers and toes. This study was designed to test intermittent dosing schedules using two dosage levels: 500 mg as a single weekly dose and 200 mg as a biweekly dose, each for 30 days. Fifteen men and women were studied in each dosing group. All were heavy smokers considered to be at high risk for developing lung cancer. Plasma, buccal mucosa cell, and lipoprotein concentrations were measured at different intervals corresponding to the time period when most of the adverse effects occur. No serious toxicities were observed using these doses and schedules. The plasma and buccal mucosa cell concentrations of Oltipraz showed substantial interindividual variations at each sampling. Some subjects had no detectable plasma or buccal mucosal cell Oltipraz concentrations. The distribution of Oltipraz incorporation into the lipid fractions and albumin was changed by the administration of different schedules of Oltipraz. The results of this study suggest that the intermittent dosing is well tolerated and does not result in steady state in plasma or buccal mucosa cells. The variation and lack of detectable Oltipraz concentration in plasma, buccal mucosa cells, and lipids may affect both the toxicity and the pharmacological effects when these doses and schedules are used.

Epidermal growth factor receptor tyrosine kinase inhibitors as potential cancer chemopreventives.

Among the most important targets for chemopreventive intervention and drug development are deregulated signal transduction pathways, and protein tyrosine kinases are key components of these pathways. Loss of tyrosine kinase regulatory mechanisms has been implicated in neoplastic growth; indeed, many oncogenes code for either receptor or cellular tyrosine kinases. Because of its deregulation in many cancers (bladder, breast, cervix, colon, esophagus, head and neck, lung, and prostate), the epidermal growth factor receptor (EGFR) has been selected as a potential target for chemoprevention. Because growth factor networks are redundant, selective inhibition of signaling pathways activated in precancerous and cancerous cells should be possible. Requirements for specific EGFR inhibitors include specificity for EGFR, high potency, activity in intact cells, and activity in vivo. Inhibition of autophosphorylation is preferred, because it should result in total blockade of the signaling pathway. Inhibitors that compete with substrate rather than at the ATP-binding site are also preferable, because they are not as likely to inhibit other ATP-using cellular enzymes. Several classes of specific EGFR inhibitors have been synthesized recently, including structures such as benzylidene malononitriles, dianilinophthalimides, quinazolines, pyrimidines, [(alkylamino)methyl]-acrylophenones, enollactones, dihydroxybenzylaminosalicylates, 2-thioindoles, aminoflavones, and tyrosine analogue-containing peptides. A possible testing strategy for the development of these and other EGFR inhibitors as chemopreventive agents includes the following steps: (a) determine EGFR tyrosine kinase inhibitory activity in vitro; (b) evaluate EGFR specificity and selectivity (relative to other tyrosine kinases and other protein kinases); (c) determine inhibition of EGFR-mediated effects in intact cells; (d) determine inhibition of EGFR-mediated effects in vivo (e.g., in nude mouse tumor xenografts); and (e) determine chemopreventive efficacy in vivo (e.g., in the hamster buccal pouch or mouse or rat bladder).

Farnesyl protein transferase inhibitors as potential cancer chemopreventives.

Among the most important targets for chemopreventive intervention and drug development are deregulated signal transduction pathways. Ras proteins serve as central connectors between signals generated at the plasma membrane and nuclear effectors; thus, disrupting the Ras signaling pathway could have significant potential as a cancer chemopreventive strategy. Target organs for Ras-based chemopreventive strategies include those associated with activating ras mutations (e.g., colorectum, pancreas, and lung) and those carrying aberrations in upstream element(s), such as growth factors and their receptors. Ras proteins require posttranslational modification with a farnesyl moiety for both normal and oncogenic activity. Inhibitors of the enzyme that catalyzes this reaction, farnesyl protein transferase (FPT) should, therefore, inhibit Ras-dependent proliferative activity in cancerous and precancerous lesions (J. B. Gibbs et al., Cell, 77: 175-178, 1994). Because growth factor networks are redundant, selective inhibition of signaling pathways activated in precancerous and cancerous cells should be possible. Requirements for Ras farnesylation inhibitors include: specificity for FPT compared with other prenyl transferases; specificity for FPT compared with other farnesyl PPi-utilizing enzymes; ability to specifically inhibit processing of mutant K-ras (the most commonly mutated ras gene in human cancers); high potency; selective activity in intact cells; activity in vivo; and lack of toxicity. Numerous FPT inhibitors have been identified through random screening of natural products and by rational design of analogues of the two substrates, farnesyl PPi and the COOH-terminal CAAX motif of Ras tetrapeptides. A possible testing strategy for developing FPT inhibitors as chemopreventive agents includes the following steps: (a) determine FPT inhibitory activity in vitro; (b) evaluate selectivity (relative to other protein prenyl transferases and FPT-utilizing enzymes); (c) determine inhibition of Ras-mediated effects in intact cells; (d) determine inhibition of Ras-mediated effects in vivo (e.g., in nude mouse tumor xenografts); and (e) determine chemopreventive efficacy in vivo (e.g., in carcinogen-induced A/J mouse lung, rat colon, or hamster pancreas).

Aromatase inhibitors as potential cancer chemopreventives.

Epidemiological and experimental evidence strongly supports a role for estrogens in the development and growth of breast tumors. A role for estrogen in prostate neoplasia has also been postulated. Therefore, one chemopreventive strategy for breast and prostate cancers is to decrease estrogen production. This can be accomplished by inhibiting aromatase, the enzyme that catalyzes the final, rate-limiting step in estrogen biosynthesis. The use of aromatase inhibitors is of clinical interest for cancer therapy, and selective, potent aromatase inhibitors have been developed. Several of these agents have demonstrated chemopreventive efficacy in animal models. The rationale for the use of aromatase inhibitors as chemopreventives and identification of inhibitors to serve as potential chemopreventive agents are the subjects of this review. After background information regarding aromatase is presented, the data for each inhibitor are summarized separately. The discussion focuses on those inhibitors that are clinically available or in clinical trials, including: aminoglutethimide (Cytadren), rogletimide, fadrozole hydrochloride, liarozole hydrochloride, anastrozole (Arimidex), letrozole, vorozole, formestane, exemestane, and atamestane. On the basis of results from preclinical studies, aromatase inhibitors may be promising agents for clinical trials in populations at high risk for developing estrogen-dependent cancers. Total suppression of aromatase may have adverse effects, as is evident in postmenopausal women (increased osteoporosis, cardiovascular disease, and urogenital atrophy). However, on the basis of preclinical studies of chemopreventive efficacy and chemotherapeutic applications of aromatase inhibitors showing dose-response efficacy, it may be possible to obtain chemopreventive effects without total suppression of aromatase and circulating estrogen levels. Suppressing local estrogen production may be an alternative strategy, as suggested by the discovery of a unique transcriptional promoter of aromatase gene expression, I.4, in breast adipose tissue. The development of drugs that target this promoter region may be possible.

Chemopreventive drug development: perspectives and progress.

Chemoprevention drug development has the goal of identifying safe and effective chemopreventive agents for clinical use. Several distinctive strategies are pursued in developing chemopreventive agents: (a) identifying and validating predysplastic and early dysplastic lesions that can be used instead of cancers as endpoints for measuring chemopreventive activity; (b) identifying and testing candidate agents based on considerations of mechanisms of action; (c) evaluating combinations of agents with potential for maximizing efficacy and minimizing toxicity; and (d) applying a systematic methodology for identifying and ranking candidate agents at each stage of development to ensure discovery of the best agents and most effective use of available resources. This article discusses 22 drugs and three drug combinations which have reached an advanced stage of development as chemopreventive agents. The first generation of drugs are the most advanced, now being in Phase II and Phase III clinical trials. These drugs include several retinoids [vitamin A, 13-cis-retinoic acid, all-trans-N-(4-hydroxyphenyl)retinamide], calcium, beta-carotene, tamoxifen, and finasteride. The second generation drugs are those in Phase I clinical trials. From most to least advanced, these drugs are 2-difluoromethylornithine, sulindac, piroxicam, oltipraz, N-acetyl-I-cysteine, aspirin, ibuprofen, carbenoxolone, 18 beta-glycyrrhetinic acid, and the combination of 2-difluoromethylornithine with piroxicam. The third generation includes agents with significant evidence of chemopreventive activity in animal models. These agents are now in preclinical toxicity testing. They are S-allyl-I-cysteine, phenhexyl isothiocyanate, curcumin, ellagic acid, fumaric acid, fluasterone, and the combinations of all-trans-N-(4-hydroxyphenyl)retinamide with oltipraz and all-trans-N-(4-hydroxyphenyl) retinamide with tamoxifen.