Randomized phase II clinical trial of avotermin versus placebo for scar improvement.

BACKGROUND: Scarring is a major problem following skin injury. In early clinical trials, transforming growth factor ß3 (avotermin) improved scar appearance. The aim of this study was to determine whether an injection of avotermin at the time of wound closure is effective in improving scar appearance. METHODS: Study RN1001-0042, a double-blind, randomized, within-patient, placebo-controlled trial, investigated the efficacy and safety of four doses of avotermin given once. Patients undergoing bilateral surgery to remove varicose leg veins by saphenofemoral ligation and long saphenous vein stripping were enrolled at 20 European centres. A total of 156 patients were randomized to receive one of four doses of avotermin (5, 50, 200 or 500 ng per 100 µl, at 100 µl per linear cm of wound margin), administered by intradermal injection to the groin and distal wound margins of one leg; placebo was administered to the other leg. Scar appearance was evaluated by an independent panel of lay people (lay panel), investigators and patients. The primary efficacy variable was lay panel Total Scar Score (ToScar), derived from visual analogue scale scores for groin scars between 6 weeks and 7 months. RESULTS: Avotermin 500 ng significantly improved groin scar appearance compared with placebo (mean lay panel ToScar difference 16·49 mm; P = 0·036). CONCLUSION: Avotermin 500 ng per 100 µl per linear cm of wound margin given once is well tolerated and significantly improves scar appearance.

Complex patterns of alternative splicing mediate the spatial and temporal distribution of perlecan/UNC-52 in Caenorhabditis elegans.

The unc-52 gene encodes the nematode homologue of mammalian perlecan, the major heparan sulfate proteoglycan of the extracellular matrix. This is a large complex protein with regions similar to low-density lipoprotein receptors, laminin, and neural cell adhesion molecules (NCAMs). In this study, we extend our earlier work and demonstrate that a number of complex isoforms of this protein are expressed through alternative splicing. We identified three major classes of perlecan isoforms: a short form lacking the NCAM region and the C-terminal agrin-like region; a medium form containing the NCAM region, but still lacking the agrin-like region; and a newly identified long form that contains all five domains present in mammalian perlecan. Using region-specific antibodies and unc-52 mutants, we reveal a complex spatial and temporal expression pattern for these UNC-52 isoforms. As well, using a series of mutations affecting different regions and thus different isoforms of UNC-52, we demonstrate that the medium NCAM-containing isoforms are sufficient for myofilament lattice assembly in developing nematode body-wall muscle. Neither short isoforms nor isoforms containing the C-terminal agrin-like region are essential for sarcomere assembly or muscle cell attachment, and their role in development remains unclear.

p53-dependent apoptosis in melanoma cells after treatment with camptothecin.

Cutaneous malignant melanoma is a life-threatening cancer with poor prognosis due to a high metastasis potential. The main obstacle in treatment of metastatic melanoma is the resistance to chemotherapy. Recent studies indicated that apoptosis is a common mechanism of action for various cytotoxic agents. As p53 plays an important part in apoptosis, we investigated the role of p53 in chemosensitivity of melanoma cells. Previously, we found that melanoma cell lines containing wild-type p53 have significantly higher response rates to chemotherapy than cell lines with a mutant p53 gene. To confirm the role of p53 in melanoma chemosensitivity further, we transfected an expression vector, pED1, which carries a mutant p53 gene, into a wild-type p53 melanoma cell line, MMAN. We examined the effect of mutant p53 on camptothecin-induced apoptosis and the expression of genes which are known to be involved in apoptosis or drug resistance, such as bcl-2, bax, bak, p21waf1, and P-glycoprotein. Our results indicate that overexpression of the mutant p53 increased the growth rate of MMAN cells, reduced the sensitivity to camptothecin, and lowered drug-induced apoptosis by 2-3-fold. Flow cytometry indicated that the camptothecin-induced apoptosis is not associated with G1 arrest. Furthermore, camptothecin treatment reduced bcl-2 and P-glycoprotein expression in wild-type p53 MMAN cells, but not cells overexpressing mutant p53. These results demonstrate that p53 mutational status is a determinant of melanoma chemosensitivity. p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.

Testosterone and cortisol in relationship to dietary nutrients and resistance exercise.

Manipulation of resistance exercise variables (i.e., intensity, volume, and rest periods) affects the endocrine response to exercise; however, the influence of dietary nutrients on basal and exercise-induced concentrations of hormones is less understood. The present study examined the relationship between dietary nutrients and resting and exercise-induced blood concentrations of testosterone (T) and cortisol (C). Twelve men performed a bench press exercise protocol (5 sets to failure using a 10-repetitions maximum load) and a jump squat protocol (5 sets of 10 repetitions using 30% of each subject's 1-repetition maximum squat) with 2 min of rest between all sets. A blood sample was obtained at preexercise and 5 min postexercise for determination of serum T and C. Subjects also completed detailed dietary food records for a total of 17 days. There was a significant (P < or = 0.05) increase in postexercise T compared with preexercise values for both the bench press (7.4%) and jump squat (15.1%) protocols; however, C was not significantly different from preexercise concentrations. Significant correlations were observed between preexercise T and percent energy protein (r = -0.71), percent energy fat (r = 0.72), saturated fatty acids (g.1,000 kcal-1.day-1; r = 0.77), monounsaturated fatty acids (g.1,000 kcal-1.day-1; r = 0.79, the polyunsaturated fat-to-saturated fat ratio (r = -0.63), and the protein-to-carbohydrate ratio (r = -0.59). There were no significant correlations observed between any nutritional variables and preexercise C or the absolute increase in T and C after exercise. These data confirm that high-intensity resistance exercise results in elevated postexercise T concentrations. A more impressive finding was that dietary nutrients may be capable of modulating resting concentrations of T.

Hormonal responses to consecutive days of heavy-resistance exercise with or without nutritional supplementation.

Nine resistance-trained men consumed either a protein-carbohydrate supplement or placebo for 1 wk in a crossover design separated by 7 days. The last 3 days of each treatment, subjects performed resistance exercise. The supplement was consumed 2 h before and immediately after the workout, and blood was obtained before and after exercise (0, 15, 30, 45, and 60 min postexercise). Lactate, growth hormone, and testosterone were significantly (P

Leukocyte adhesion molecule expression during intense resistance exercise.

We hypothesized that expression of L-selectin and very late antigen-4 (VLA-4) integrin adhesion molecules would influence cell type-specific redistribution during exercise. Women subjects performed six sets of 10-repetition maximum squats. L-selectin and VLA-4 integrin were measured by using flow cytometry pre- and postexercise on peripheral blood neutrophils and lymphocytes (n = 29 subjects) and lymphocyte subsets (n = 70 subjects), respectively. Neutrophil concentration increased 41.8% (P < 0.001), whereas the percent expressing L-selectin was unchanged (79%). Lymphocyte concentration increased 61.8% (P < 0.001). The percent of T cells expressing L-selectin decreased from 73.5 +/- 8.9 to 68.2 +/- 11.4% (P < 0.001); the combined population of natural killer and B cells expressing L-selectin decreased from 80.4 +/- 22.5 to 62.7 +/- 25.8% (P < 0.001). VLA-4 integrin was expressed by nearly all lymphocytes both pre- and postexercise. The proportional decrease in L-selectin positive cells could have resulted from 1) shedding of L-selectin, 2) selective entry of L-selectin-negative subsets, or 3) selective removal of L-selectin-positive subsets.

Plasma proenkephalin peptide F and human B cell responses to exercise stress in fit and unfit women.

In vitro studies have connected immune cell function to Peptide F. The primary purpose of this investigation was to examine the responses of plasma Peptide F and epinephrine along with the changes in B cell antibody production in vivo in physically fit and unfit women in response to physical exercise on a cycle ergometer at 60% and 80% of peak oxygen consumption. Seven aerobically fit and eight untrained (i.e., unfit) women between the ages of 18 and 30 volunteered to participate in this investigation. Blood samples (analyzed for plasma Peptide F and epinephrine along with the number of antibody-producing B cells) were obtained 24 hours prior to the exercise session, pre-exercise, during each exercise intensity, and five minutes post-exercise. The fit group had a significantly higher plasma Peptide F concentration after the 80% exercise intensity along with significantly higher numbers of antibody producing B cells compared to the unfit group. The results of this investigation show that physically fit women have an enhanced secondary response of B cells to a specific antigen under conditions where Peptide F is increased. Such data demonstrate that physical fitness as promoted by the Public Health Service (e.g., Healthy People 2000) influences the underlying hormonal and immune cell responses when challenged by physical exercise stress.

Neuromuscular disturbance outlasts other symptoms of exercise-induced muscle damage.

This study examined the biochemical, immunological, functional, and neuromuscular responses associated with exercise-induced muscle damage in the quadriceps of untrained men. Muscle damage and soreness was elicited with maximal concentric/eccentric muscle actions at 0.53 rads s(-1). Significant (P<0.05) soreness was evident 1, 2, and 3 days following muscle insult, while plasma creatine kinase, a marker of muscle damage, was elevated 3 and 5 days post-insult. Plasma interleukin-Ibeta was significantly increased within 5 min, and remained elevated 1, 2, 5, and 7 days post-insult. Maximal isometric quadriceps function was impaired (P<0. 05) for 5 days following muscle challenge. Maximal isokinetic performance at 1.09 rads s(-1) was diminished (P<0.05) for 2 days post-insult; no significant decrements at 3.14 rads s(-1) were noted. Average electrical activation (iEMG) of the quadriceps was unaltered, but iEMG activity of the rectus femoris - where soreness was focused - was significantly increased. Neuromuscular efficiency (torque/iEMG) was compromised throughout the 10-day post-insult period investigated. While other symptoms of exercise-induced muscle damage dissipate within 7 days, neuromuscular perturbation persists for at least 10 days.

Effect of N-acetylcysteine on UVB-induced apoptosis and DNA repair in human and mouse keratinocytes.

The incidence of skin cancer is increasing rapidly, particularly in the Caucasian population. Epidemiological and experimental studies demonstrated that ultraviolet radiation (UVR) is the primary cause for the increasing incidence of skin cancer. It is well known that UV irradiation induces DNA damage. If the damage is not repaired or removed in time, it can lead to mutations and skin carcinogenesis. N-acetylcysteine (NAC) has been shown to be an effective protector against UVB-induced immunosuppression and to modulate the expression of some oncogenes and tumor suppressor genes. To test further the protective effect of NAC against UVR, we used both in vitro and in vivo models to investigate the effect of NAC on UVB-induced apoptosis and repair of DNA damage in human and mouse keratinocytes. Our data indicate that the intracellular glutathione level was increased after treatment with NAC at 10-20 mM but decreased with 40 mM NAC treatment due to the toxicity. At concentrations up to 20 mM NAC did not have a significant effect on UVB-induced apoptosis of cultured human keratinocytes. In addition, in an in vivo mouse model, topical application of NAC (3 mumol cm-2) that has been shown to inhibit UVB-induced immunosuppression did not have any effect on UVB-induced apoptosis and did not reduce the formation or enhance the repair of UVB-induced cyclobutane pyrimidine dimers and (6-4) photoproducts. Our results indicate that NAC is ineffective in preserving the genomic stability of keratinocytes against UVB irradiation.

Creatine supplementation enhances muscular performance during high-intensity resistance exercise.

OBJECTIVE: This study was undertaken to investigate the influence of oral supplementation with creatine monohydrate on muscular performance during repeated sets of high-intensity resistance exercise. SUBJECTS/DESIGN: Fourteen active men were randomly assigned in a double-blind fashion to either a creatine group (n = 7) or a placebo group (n = 7). Both groups performed a bench press exercise protocol (5 sets to failure using each subject's predetermined 10-repetition maximum) and a jump squat exercise protocol (5 sets of 10 repetitions using 30% of each subject's 1-repetition maximum squat) on three different occasions (T1, T2, and T3) separated by 6 days. INTERVENTION: Before T1, both groups received no supplementation. From T1 to T2, both groups ingested placebo capsules. From T2 to T3, the creatine group ingested 25 g creatine monohydrate per day, and the placebo group ingested an equivalent amount of placebo. MAIN OUTCOME MEASURES: Total repetitions for each set of bench presses and peak power output for each set of jump squats were determined. Other measures included assessment of diet, body mass, skinfold thickness, and preexercise and 5-minute postexercise lactate concentrations. RESULTS: Lifting performance was not altered for either exercise protocol after ingestion of the placebos. Creatine supplementation resulted in a significant improvement in peak power output during all 5 sets of jump squats and a significant improvement in repetitions during all 5 sets of bench presses. After creatine supplementation, postexercise lactate concentrations were significantly higher after the bench press but not the jump squat. A significant increase in body mass of 1.4 kg (range = 0.0 to 2.7 kg) was observed after creatine ingestion. CONCLUSION: One week of creatine supplementation (25 g/day) enhances muscular performance during repeated sets of bench press and jump squat exercise.

Exercise and recovery responses of adrenal medullary neurohormones to heavy resistance exercise.

PURPOSE: The purpose of this study was to examine the effect of dynamic resistance exercise on the response patterns of adrenal medullary neurohormones in strength-trained men. METHODS: Ten strength-trained men (21.7+/-0.58 yr) gave informed consent and performed two resistance exercise protocols, high force and high power, of equal total work in a randomized order separated by 1 wk. Blood samples were obtained pre-exercise (baseline), 0 (R-0), 15 (R-15), and 240 (R-240) min postexercise and under resting control conditions for each time point. RESULTS: There were no significant differences in control concentrations for each time point and no difference in pre-exercise values between the two resistance exercise protocols for plasma lactate, epinephrine, plasma peptide F (P-F), or norepinephrine (NE). Plasma lactate significantly (P< or = 0.05) increased from baseline for both protocols; however, concentrations were higher in response to the high force protocol. Plasma epinephrine was significantly increased from baseline at R-0 and returned to baseline at R-15 for both protocols. In contrast, plasma P-F was significantly decreased at R-0 from baseline; however, at R-240 P-F had significantly increased to >80% baseline for both protocols. CONCLUSIONS: These results indicate that the adrenal medulla was activated in response to the acute stress of both types of heavy resistance exercise. Furthermore, during longer recovery periods, the adrenal medulla was also active above baseline conditions as increased concentrations of proenkephalin fragments (i.e., P-F) were detected in the circulation.

Biorhythmic influences on functional capacity of human muscle and physiological responses.

UNLABELLED: Previously, this laboratory has demonstrated that exhaustive aerobic exercise performance is not subject to significant chronobiological variation between 0800 and 2000 h, but certain physiological responses to maximal aerobic effort do fluctuate significantly within that time frame. PURPOSE: The purpose of the present investigation was to determine whether muscle performance, and selected physiological responses to resistance exercise, was significantly influenced by time of day effects. METHODS: Ten healthy, but untrained, men (21.1+/-0.6 yr, mean +/- SE) volunteered to participate in the study. In a balanced and randomized study design, each subject performed resistance exercise protocols on an isokinetic dynamometer with maximal effort at 0800 h, 1200 h, 1600 h, and 2000 h. Selected physiological and hormonal data were recorded before and immediately following the exercise stimulus. RESULTS: The data demonstrated significant chronobiological oscillation in peak torque, average power, maximal work in a single repetition, and total work per set. Interestingly, this oscillation was manifested only at the fastest velocities of limb movement utilized. Pre- and postexercise rectal temperature exhibited significant time of day fluctuation, as did postexercise blood pressure. Plasma levels of testosterone and cortisol also displayed significant biorhythmicity under both pre- and postexercise conditions. However, exercise-induced responses (pre- to postexercise differences) of those steroid hormones did not exhibit significant biorythmic variation. Although plasma concentrations of both testosterone and cortisol were highest at 0800 h, testosterone to cortisol ratios were greatest at 2000 h. CONCLUSIONS: In summary, these data suggest that maximal muscle performance does vary within the segment of the day when exercise typically occurs (0800-2000 h) but that this variation is specific to speed of movement.

Influence of compression hosiery on physiological responses to standing fatigue in women.

PURPOSE: The purpose of this investigation was to examine the influence of various designs of commercial hosiery, which use graduated compression, on the physiological and performance responses to standing fatigue. METHODS: Twelve healthy women (age = 23.0+/-2.1 yr, height = 165.7+/-5.0 cm, percent body fat = 22.6+/-4.2%, body mass = 60.0+/-8.9 kg) volunteered to participate in this investigation. All subjects completed four identical standing fatigue protocols with different garment conditions each separated by 7 d. The standing fatigue protocol involved a total of 8 h of standing on hard floors during which subjects participated in various tasks and experimental testing procedures. In addition, all activity and dietary profiles of the subjects were carefully controlled 48 h before each experimental session. Before the standing fatigue protocol, subjects completed a battery of tests to establish morning baseline values. Experimental tests included determination of lower leg venous cross-sectional area, blood pressure, heart rate, perceived discomfort ratings, circumferences measurements, total body water, variation in center of pressure during "quiet" standing, vertical jump performance, and specific regional patterns of foot pressures. RESULTS: This investigation demonstrated that commercial hosiery with various forms of graduated compression and construction were effective in mediating a reduction in edema in the ankles and legs while reducing the amount of venous pooling and discomfort in the lower body. Different constructions of garments may mediate these overall effects via different physiological mechanisms related to fluid shifts and muscle tissue damage. CONCLUSION: Wearing various types of graduated compression hose during the day as it relates to women in standing professions may minimize edema and muscle tissue disruption, thereby increasing comfort in the legs.

Influence of exercise training on physiological and performance changes with weight loss in men.

PURPOSE: The purpose of this study was to examine the physiological effects of a weight-loss dietary regimen with or without exercise. METHODS: Thirty-five overweight men were matched and randomly placed into either a control group (C; N = 6) or one of three dietary groups; a diet-only group (D; N = 8), a diet group that performed aerobic exercise three times per week (DE; N = 11); and a diet group that performed both aerobic and strength training three times per week (DES; N = 10). RESULTS: After 12 wk, D, DE, and DES demonstrated a similar and significant (P < or = 0.05) reduction in body mass (-9.64, -8.99, and -9.90 kg, respectively) with fat mass comprising 69, 78, and 97% of the total loss in body mass, respectively. The diet-only group also demonstrated a significant reduction in fat-free mass. Maximum strength, as determined by 1-RM testing in the bench press and squat exercise was significantly increased for DES in both the bench press (+19.6%) and squat exercise (+32.6%). Absolute peak O2 consumption was significantly elevated in DE (+24.8%) and DES (+15.4%). There were no differences in performance during a 30-s Wingate test for the DE and DES, whereas D demonstrated a significant decline in peak and mean power output. Resting metabolic rate (RMR) (kcal x d(-1)) was not significantly different for any of the groups except for the DE group. There were no significant changes in basal concentrations of serum glucose, BUN, cortisol, testosterone, and high density lipoprotein (HDL) cholesterol for any of the groups. Serum total cholesterol and low density lipoprotein (LDL) cholesterol were significantly decreased for all dietary groups. Serum triglycerides were significantly reduced for D and DES at week 6 and remained lower at week 12 for D, while triglycerides returned to baseline values for DES. CONCLUSIONS: These data indicate that a weight-loss dietary regimen in conjunction with aerobic and resistance exercise prevents the normal decline in fat-free mass and muscular power and augments body composition, maximal strength, and maximum oxygen consumption compared with weight-loss induced by diet alone.

Low-volume circuit versus high-volume periodized resistance training in women.

PURPOSE: The purpose of this investigation was to determine the long-term training adaptations associated with low-volume circuit-type versus periodized high-volume resistance training programs in women. METHODS: 34 healthy, untrained women were randomly placed into one of the following groups: low-volume, single-set circuit (SSC; N = 12); periodized high-volume multiple-set (MS; N = 12); or nonexercising control (CON) group (N = 10). The SSC group performed one set of 8-12 repetitions to muscular failure 3 d x wk(-1). The MS group performed two to four sets of 3-15 repetitions with periodized volume and intensity 4 d x wk(-1). Muscular strength, power, speed, endurance, anthropometry, and resting hormonal concentrations were determined pretraining (T1), after 12 wk (T2), and after 24 wk of training (T3). RESULTS: 1-RM bench press and leg press, and upper and lower body local muscular endurance increased significantly (P < or = 0.05) at T2 for both groups, but only MS showed a significant increase at T3. Muscular power and speed increased significantly at T2 and T3 only for MS. Increases in testosterone were observed for both groups at T2 but only MS showed a significant increase at T3. Cortisol decreased from T1 to T2 and from T2 to T3 in MS. Insulin-like growth factor-1 increased significantly at T3 for SSC and at T2 and T3 for MS. No changes were observed for growth hormone in any of the training groups. CONCLUSION: Significant improvements in muscular performance may be attained with either a low-volume single-set program or a high-volume, periodized multiple-set program during the first 12 wk of training in untrained women. However, dramatically different training adaptations are associated with specific domains of training program design which contrast in speed of movement, exercise choices and use of variation (periodization) in the intensity and volume of exercise.

Resistance training combined with bench-step aerobics enhances women's health profile.

PURPOSE: The purpose of this study was to investigate the comprehensive physiological alterations that take place during the combination of bench-step aerobics (BSA) and resistance exercise training. METHODS: Thirty-five healthy, active women were randomly assigned to one of four groups that either a) performed 25 min of BSA only (SA25); b) performed a combination of 25 min of BSA and a multiple-set upper and lower body resistance exercise program (SAR); c) performed 40 min of BSA only (SA40); or d) served as a control group (C), only performing activities of daily living. Direct assessments for body composition, aerobic fitness, muscular strength, endurance, power, and cross-sectional area were performed 1 wk before and after 12 wk of training. RESULTS: All training groups significantly improved peak VO(2) (3.7 to 5.3 mL O(2).kg(-1).min(-1)), with the greatest improvement observed in the SAR group (P = 0.05). Significant reductions in preexercise heart rates (8-9 bpm) and body fat percent (5--6%) were observed in all training groups after training. Significant reductions in resting diastolic blood pressure were observed for the SAR and SA40 groups (6.7 and 5.8 mm Hg, respectively). Muscular strength and endurance only improved significantly in the SAR group (21 and 11% respectively). All groups demonstrated increased lower body power (11--14%), but only the SAR group significantly improved upper body power (32%). Thigh muscle cross-sectional areas measured via magnetic resonance imaging (MRI) increased primarily for the SAR group. CONCLUSION: BSA is an exercise modality effective for improving physical fitness and body composition in healthy women. The addition of resistance exercise appears to enhance the total fitness profile by improving muscular performances, muscle morphology, and cardiovascular fitness greater than from performing BSA alone. Therefore, the inclusion of both modalities to an exercise program is most effective for improving total body fitness and a woman's health profile.

Effect of resistance training on women's strength/power and occupational performances.

PURPOSE: The effects of resistance training programs on strength, power, and military occupational task performances in women were examined. METHODS: Untrained women aged (mean +/- SD) 23 +/- 4 yr were matched and randomly placed in total- (TP, N = 17 and TH, N = 18) or upper-body resistance training (UP, N = 18 and UH, N = 15), field (FLD, N = 14), or aerobic training groups (AER, N = 11). Two periodized resistance training programs (with supplemental aerobic training) emphasized explosive exercise movements using 3- to 8-RM training loads (TP, UP), whereas the other two emphasized slower exercise movements using 8- to 12-RM loads (TH, UH). The FLD group performed plyometric and partner exercises. Subjects were tested for body composition, strength, power, endurance, maximal and repetitive box lift, 2-mile loaded run, and U.S. Army Physical Fitness Tests before (T0) and after 3 (T3) and 6 months of training (T6). For comparison, untrained men (N = 100) (MEN) were tested once. RESULTS: Specific training programs resulted in significant increases in body mass (TP), 1-RM squat (TP, TH, FLD), bench press (all except AER), high pull (TP), squat jump (TP, TH, FLD), bench throw (all except AER), squat endurance (all except AER), 1-RM box lift (all except aerobic), repetitive box lift (all), push-ups (all except AER), sit-ups (all except AER), and 2-mile run (all). CONCLUSIONS: Strength training improved physical performances of women over 6 months and adaptations in strength, power, and endurance were specific to the subtle differences (e.g., exercise choice and speeds of exercise movement) in the resistance training programs (strength/power vs strength/hypertrophy). Upper- and total-body resistance training resulted in similar improvements in occupational task performances, especially in tasks that involved upper-body musculature. Finally, gender differences in physical performance measures were reduced after resistance training in women, which underscores the importance of such training for physically demanding occupations.

Sandramycin, a novel antitumor antibiotic produced by a Nocardioides sp. Production, isolation, characterization and biological properties.

A new antitumor antibiotic, sandramycin, was isolated from cultured broth of a Nocardioides sp. (ATCC 39419) and purified by solvent partition and column chromatography. Sandramycin, a new depsipeptide, was moderately active in vitro against Gram-positive organisms and in vivo against leukemia P388 in mice.

Production and biological activity of marcellomycin, an antitumor anthracycline antibiotic, and taxonomy of the producing organism.

An actinomycete, isolated from a soil sample from Ontario, Canada, was studied taxonomically and named Actinosporangium bohemicum sp. nov. strain C-36,145. This strain was found to produce a complex mixture of e-pyrromycinone glycosides having antitumor properties. Marcellomycin, a member of this complex, was selected for further study. Conditions for production of this antibiotic were developed in flask studies and scaled-up to the 3,000-liter fermentor stage.

Production and biological activity of rebeccamycin, a novel antitumor agent.

An actinomycete, strain C-38,383, was selected in a screening program for the isolation of novel antitumor agents. A yellow crystalline product, named rebeccamycin, was isolated from the mycelium and was found to have activity against P388 leukemia, L1210 leukemia and B16 melanoma implanted in mice. Rebeccamycin inhibits the growth of human lung adenocarcinoma cells (A549) and produces single-strand breaks in the DNA of these cells. No DNA-protein cross-links were detected. A related antibiotic, staurosporine, is produced by Streptomyces staurosporeus and Streptomyces actuosus. Strain C-38,383 was found to resemble closely strains of Nocardia aerocolonigenes recently renamed Saccharothrix aerocolonigenes. A strain selection isolate without aerial mycelium, C-38,383-RK-1, failed to produce rebeccamycin while a strain with aerial mycelium, C-38,383-RK-2, was found to be a suitable strain for production. A description of the producing strain is presented and its taxonomic position is reviewed. A fermentor containing 37 liters of production medium gave a rebeccamycin yield of 663 mg/liter after 204 hours of incubation with strain C-38,383-RK-2.