Poly(L-lactide) and poly(butylene succinate) immiscible blends: from electrospinning to biologically active materials.

For the first time the preparation of defect-free fibers from immiscible blends of high molar mass poly(lactic acid) (PLA) and poly(butylene succinate) (PBS) in the whole range of the polyester weight ratios is shown. Electrospinning using the solvent-nonsolvent approach proved most appropriate. Moreover, electrospinning revealed crucial for the obtaining of PLA/PBS materials maintaining integrity. DSC and XRD analyses attested for a plasticizing effect and for increased PLA crystallinity at PBS addition to PLA. The mechanical properties of the PLA/PBS mats were controlled by the alignment of the fibers and changed from plastic to brittle materials upon increasing the PBS content. Drug loading and tests against pathogenic microorganisms suggested that the obtained mats can find application as antibacterial fibrous materials.

4 Nitroquinoline 1-oxide-induced carcinogenesis in the rat palate.

Most reported studies of experimental oral cancer have been carried out in the hamster. This animal is not available in certain countries and there is controversy regarding its suitability as a model for experimental oral carcinogenesis. An attempt was made to reproduce an experimental oral cancer model in rats, using a protocol based on that described by Lekholm and Wallenius (1976). The carcinogen 4 nitroquinoline 1-oxide was applied to the palates of rats for periods of up to 24 weeks. Macroscopic and microscopic examination of carcinogen-treated palatal mucosa was carried out during the experimental period. Verrucous carcinoma-like lesions of the mid-palate and squamous carcinomas of the gingival mucosa were produced, beginning at 16 and 20 weeks respectively. A variety of other macroscopic and microscopic mucosal changes were also observed during the experimental period. The findings are discussed in relation to the work of others.

Difference in the induction of osteosarcoma in rabbit bone with single administration of three kinds of chemical carcinogens.

A single intramedullary administration of each dose (15 approximately 20 mg) of 4-nitroquinoline 1-oxide, 3-methylcholanthrene, or 7,12-dimethylbenz[alpha]anthracene was applied to the mandible, diaphysis, or distal metaphysis of the femur of rabbits. The highest incidence in production of osteosarcoma was obtained from the group in which 4-nitroquinoline 1-oxide was applied to the distal metaphysis (75%, including one case of chondrosarcoma). Tumors hardly appeared in any of the groups when given 3-methylcholanthrene or 7,12-dimethylbenz[alpha]anthracene. Histologically, three kinds of entities were recognized from the quantitative difference of the reactive tissues which appeared around carcinogens. It is estimated that the condition of entity III induces the highest incidence of osteosarcoma if chemical carcinogens are given into the bone marrow of experimental animals.

Experimental production of osteogenic sarcoma of the mandible in rabbits with 4-nitroquinoline 1-oxide.

A single intramedullary administration of 4-nitroquinoline 1-oxide (4-NQO) into the mandible in 32 rabbits induced 21 cases of osteogenic sarcoma (65.6%), 5 chondrosarcoma (15.6%), 2 fibrosarcomas, and 3 cementoblastomas. None of the tumors appeared until the 3rd month after the treatment. From the 4th to 6th month, early stages of osteogenic tumors were seen. In the late stadium, from 7th to 12th month, tumors showed prominent proliferation and invasion to the oral cavity and surrounding areas. Metastasis to the lung and liver was found in 2 cases of osteogenic sarcoma.

Comparison of lung cancer and amyloidosis in rabbits induced by chemical carcinogens.

For the purpose of inducing experimental lung cancer, carcinogens were applied into the bronchus of the rabbit. Experiments were divided into 2 groups, I and II, depending on the methods of application of chemical carcinogens into the bronchus. In Experiment I, carcinogens (4-nitroquinoline 1-oxide and/or 3-methylcholanthrene) in rabbit plasma or distilled water were instilled in the lower bronchus and, in Experiment II, 3-methylcholanthrene in Tween 60 was swabbed on the maon bronchus through a specially made bronchoscope. (1) In Experiment I, 163 of 366 rabbits having received over 4 instillations of the chemical carcinogens and surviving for more than 30 days developed lung cancer. However, in Experiment II, only 2 of 65 rabbits surviving more than 60 days developed lung cancer. (2) In Experiment II, 39 (60%) of 65 rabbits were found to have developed amyloidosis. However, in Experiment I, 86 (approx. 23%) of 366 rabbits developed amyloidosis. Amyloidosis was observed to occur in the kidneys, spleen, liver, and adrenals in both experiments.

Dose-response relationship in complete oral 4NQO-carcinogenesis in rats.

Groups of 48 Wistar rats were subjected to thrice-weekly palatal application of the carcinogen 4-nitro-quinoline 1-oxide (4NQO) in propylene glycol 18, 12, 6 or 2 times, each 255 nmol 4NQO, in order to examine the relationship between the dose of the carcinogen and the tumour response. Other groups were treated with solvent alone or were left untreated. When the carcinogen was applied 18 or 12 times, squamous cell or verrucous carcinomas developed in 50% of the rats in 11 and 12 months, respectively, whereas rats subjected to the carcinogen 6 times demonstrated a 50% cancer rate in 23 months. Rats twice exposed to the carcinogen demonstrated a tumour rate of 25% in 30 months. Decreasing doses of 4NQO thus prolonged the latency period and decreased the tumour rate. The tumour development in the animals subjected to two carcinogen applications was significantly different from the tumour development among the solvent-treated animals, indicating that application of 255 nmol may approximate the initiating dose of 4NQO to be used in a two- or multi-stage carcinogenesis protocol. Most of the carcinomas, either squamous cell or verrucous, were located to the hard palate and to the gingival region of the upper jaw. Impaction of hair, bedding material and food was thought to promote the carcinogenic process.

Verrucous hyperplasia and verrucous carcinoma of the rat oral mucosa. Experimental oral carcinogenesis using 4-nitroquinoline 1-oxide.

Verrucous hyperplasia and carcinoma are recognized entities in the human pathology, but not documented experimentally. During application of the carcinogen 4-nitroquinoline 1-oxide to the oral cavity of rats three times a week for a maximum of 18 weeks an increasing frequency of verrucous hyperplasias and carcinomas were noted. The majority of the carcinomas were localized to the palate and 3/4 of these were verrucous carcinomas, with or without anaplastic transformation to infiltrating squamous cell carcinomas. The oral verrucous lesions have all the histological characteristics of their human counterparts. The present experimental study supports the idea that tobacco consumption may represent an important etiological factor in the development of human, oral verrucous carcinomas.

Sebaceous metaplasia of rat oral epithelium during chemical carcinogenesis.

Application of the carcinogen 4-nitroquinoline N-oxide (4NQO) thrice weekly to rat oral mucosa led to development of free sebaceous glands in 91% of all carcinogen-treated animals. The palatal epithelium was the area of predilection. The entire process from the transformation of single basal cells to the formation of the multi-alveoli sebaceous glands could be followed in detail. Solvent-treated animals demonstrated only a few sebaceous glands in the gingiva of the maxillary first molars whereas control animals seemed devoid of these structures. It is suggested that de novo formation of free oral sebaceous glands is caused by a metaplastic process due to local irritants among which the carcinogen 4NQO seems particularly powerful. A correlation between sebaceous metaplasia and carcinogenesis could be demonstrated.

A relationship found between intra-oral sites of 4NQO reductase activity and chemical carcinogenesis.

Topical application on rat oral mucosa of the chemical 4-nitroquinoline 1-oxide (4NQO) has been shown to produce squamous cell carcinomas on the posterior tongue and/or the posterior hard palate. 4NQO is broken down in vivo by a diaphorase, 4NQO reductase (E.C.1.6.99.2), to produce an active molecule believed to be responsible for carcinogenesis. It has been shown that there are higher concentrations of 4NQO reductase in oesophageal mucosa compared with elsewhere in the gastrointestinal tract. The purpose of these experiments was to compare the distribution of certain diaphorases in the oral mucosa. Samples of rat tongue and cheek epithelia were homogenized, then ultracentrifuged to provide mixed cytosol and microsome fractions from the epithelial cells. A spectrophotometer was used to measure the variation in absorbance at 340 nm of NADH consumed by reduction of 4NQO by enzymes present in the tissue extracts. A histochemical technique was used to compare the activity of NADH diaphorase, NADP diaphorase and glucose-6-phosphate dehydrogenase at different sites of the oral mucosa. Statistical analysis showed that there were significant (P less than 0.01) differences between the activities of all three enzymes at different sites of the oral mucosa. In each case, a higher activity was found at the sites of high incidence of squamous cell carcinoma. A lower activity was found at sites where carcinomas did not occur.

Cell population kinetics in rat palatal epithelium treated with the carcinogen 4-nitroquinoline N-oxide (4NQO).

The carcinogen 4NQO was applied to the palates of rats for 2 weeks or 2 months. Eight weeks after termination of carcinogen application, animals were injected with colchicine and sacrificed at intervals of 3 h during a 24 h period. Histological sections were produced and the number of arrested metaphases counted in the palatal epithelium. The two groups had the same daily mitotic rate and exhibited a circadian rhythm in mitotic activity similar to that demonstrated in normal oral mucosa of nocturnal animals. Carcinogen was applied to the palates of other groups of rats for 2 weeks or 2 months. Animals treated with saline served as controls. At various time points during and after carcinogen treatment eight rats from each group were killed. Four of these animals were injected with colchicine prior to sacrifice and the number of arrested metaphases counted in the palatal epithelium. In the noncolchicinized rats all mitotic phases were counted. After cessation of carcinogen application the mitotic rates, the mitotic counts and the mitotic durations did not differ from those of control animals, indicating that the carcinogen had failed to induce irreversible changes in the cell population kinetics of the palatal epithelium.

Histomorphometric analysis of epithelial changes in chemically induced oral mucosal carcinogenesis in rats.

Quantitative analysis of rat palatal mucosa after the carcinogen 4- nitroquinoline-1-oxide had been applied to the epithelium for varying periods of time showed that there was a significant increase in epithelial thickness, due largely to an increase in thickness of the basal compartment. This alteration was measurable before epithelial dysplasia could be recognised.