Advances in cancer therapy with plant based natural products.

Natural Products have long been a fertile source of cure for cancer, which is projected to become the major causes of death in this century. However, there is a continuing need for development of new anticancer drugs, drug combinations and chemotherapy strategies, by methodical and scientific exploration of enormous pool of synthetic, biological and natural products. There are at least 250,000 species of plants out of which more than one thousand plants have been found to possess significant anticancer properties. While many molecules obtained from nature have shown wonders, there are a huge number of molecules that still either remains to be trapped or studied in details by the medicinal chemists. The article reviews many such structures and their related chemistry along with the recent advances in understanding mechanism of action and structure-function relationships of nature derived anti-cancer agents at the molecular, cellular and physiological levels. Taxol, one of the most outstanding agents, has been found beneficial in treatment of refractory ovarian, breast and other cancers. Another prominent molecule includes Podophyllotoxin. Synthetic modification of this molecule led to the development of Etoposide, known to be effective for small cell cancers of the lungs and testes. Camptothecin isolated from Camptotheca acuminata also have been extensively studied. Other important molecules discussed include Vincristine, Vinblastine, Colchicine, Ellipticine and Lepachol along with Flavopiridol, a semi-synthetic analogue of the chromone alkaloid Rohitukine from India, a pyridoindole alkaloid from leaves of Ochrosia species and many more. The review also deals with the lesser-known plants of sub-Himalayan region.

Synthesis and biological properties of 4-amino- and 4-bromo-4-norpyridoxol. New approaches for the modification of the 4 position of vitamin B6.

4-Amino-4-norpyridoxol, a new key intermediate for the modification of the 4 position of vitamin B6, has been obtained by an unusual photochemical rearrangement of pyridoxal oxime. It has also been synthesized starting from 3,-alpha5-O-dibenzylpyridoxal, which was converted to 3,alpha5-O-dibenzylpyridoxamide. The latter, on Hoffman reaction, gave the desired 3,5-blocked 4-amino derivative. Several derivatives of this analogue have been prepared, and its existence in the amino tautomeric form has been established by NMR spectroscopy. A modified Sandmeyer reaction on 4-amino-4-norpyridoxol gave the 4-bromo analogue, which was found to be moderately active as an inhibitor of mouse mammary adenocarcinoma cells grown in cell culture, whereas the 4-amino analogue was not active at 10(-4)M. Other analogues containing electron-withdrawing and electron-donating substituents in the 4 position of pyridoxine were also tested.

Potential central nervous system antineoplastic agents. Amides of 6-cyano-6-norlysergic acid.

A group of amides of 6-cyano-6-norlysergic acid was prepared from their corresponding lysergamides. None of these N-cyano derivatives showed anticancer activity against lymphoid leukemia L1210 in mice. This is in contrast to the reported in vitro anticancer activity (P-815 mastocytoma) of 6-cyano-6-norlysergic acid diethylamide.

Sterol-side chain cleavage by fusants ofAlkaligenes foecalis andArthrobacter oxydans.

Protoplasts of a strain ofA. foecalis incapable of utilizing beta-sitosterol as carbon source for growth were fused with protoplasts ofA. oxydans - a strain capable of complete degradation of beta-sitosterol. Five fusants showing morphology and pattern of transformation of C-19 steroids identical toA. Foecalis were selected. Analysis of the fermentation broth containing beta-sitosterol showed that the fusants were capable of utilizing beta-sitosterol for growth but their pattern of metabolite formation from beta-sitosterol was different from that ofA. oxydans. The study revealed that the protoplast fusion technique could be used for intergeneric transfer of genetic determinants linked to partial cleavage of beta-sitosterol side chain toA. foecalis fromA. oxydans.

In vitro transformation of ampicillin to cephalexin by free and immobilized cells of Streptomyces sp.

In vitro transformation of ampicillin to cephalexin was studied using calcium alginate-immobilized and free Streptomyces sp. strain DRS-1 packed in glass columns. Tris-HCl buffer containing ampicillin was continuously circulated through the columns for four cycles, each cycle (with fresh ampicillin) being continued for 5 h. The pattern of product formation was identical in both cases, i.e. in each cycle, after reaching a certain concentration, its formation did not increase. Product formation was always higher with immobilized cells. Conversion of ampicillin to cephalexin by the strain was affected by cell and substrate concentration.

Characterization of Streptomyces sp. strain DRS-1 and its ampicillin transformation product.

Incubation of ampicillin with whole cells of Streptomyces sp. DRS-1 resulted in accumulation of four compounds different from ampicillin. One of them was isolated, purified and partially characterized. On the basis of spectroscopic characteristics, RF value and antibacterial activity the compound was identified as cephalexin. It could also be obtained from ampicillin by using crude protein extract of the strain.

Extracellular polysaccharide production by Azorhizobium caulinodans from stem nodules of leguminous emergent hydrophyte Aeschynomene aspera.

The Azorhizobium caulinodans isolated from the stem nodules of a leguminous emergent hydrophyte, Aeschynomene aspera, produced a large amount of extracellular polysaccharides (EPS) in yeast extract basal medium. Maximum EPS production was at the stationary phase of growth. EPS production was increased by 919% over control when the medium was supplemented with sucrose (1.5%), D-biotin (1 microgram/ml) and casamino acid (0.1%). EPS contained rhamnose and arabinose. Possible role of the azorhizobial EPS production in the stem nodule symbiosis is discussed.

Growth behaviour and bioproduction of indole acetic acid by a Rhizobium sp. isolated from root nodules of a leguminous tree Dalbergia lanceolaria.

The Rhizobium sp. isolated from healthy and mature root nodules of a leguminous tree, Dalbergia lanceolaria Linn. f., preferred mannitol and KNO3 for growth as carbon and nitrogen sources, respectively. The bacterium produced a high amount (22.3 microg/ml) of indole acetic acid (IAA) from L-tryptophan supplemented basal medium. Growth and IAA production started simultaneously. IAA production was maximum at 20 hr when the bacteria reached the stationary phase of growth. Cultural requirements were optimized for maximum growth and IAA production. The IAA production by the Rhizobium sp. was increased by 270.8% over control when the medium was supplemented with mannitol (1%,w/v), SDS (1 microg/ml), L-asparagine (0.02%,w/v) and biotin (1 microg/ml) in addition to L-tryptophan (2.5 mg/ml). The possible role of IAA production in the symbiosis is discussed.

An epidemiological study of the incidence of salmonellas in pigs.

The incidence of salmonellas in pigs was studied in five farms and a bacon factory.Persistence and spread of salmonella excretion in pigs in a breeding establishment is described. Salmonella excretor boars and sows were responsible for the spread and perpetuation of infection in the farm. The possibility of spreading salmonella infection between farms through the distribution of excretor pigs was studied. Infection persisted and was related to the initial state of excretion of the pigs while at the farm of origin.The importance of feeding stuffs as a source of salmonella infection in pigs is discussed. Specially prepared heat treated pellets fed to the pigs prevented the introduction of salmonellas.

Prevalence of Bacillus cereus in the faeces of healthy adults.

In a survey designed to determine the prevalence of Bacillus cereus in the faeces of healthy persons, the organism was found in low numbers in 100 (14%) of single faecal specimens from 711 adults in the general population. In addition, in an attempt at assessing the changes in the B. cereus distribution within the faecal flora of the individual, weekly faecal specimens were submitted over a seven-week period by 18 members of staff of two laboratories. The total isolation rate was again 14%, with 15 serotypes represented. In four individuals B. cereus was isolated in two consecutive weeks and in all cases the isolates were of different serotypes. Excretion was never recorded for more than two consecutive weeks. These findings probably reflect the intake of B. cereus in the individual's diet.

Indole acetic acid and its metabolism in root nodules of a monocotyledonous tree Roystonea regia.

A monocotyledonous tree, Roystonea regia, was found to bear root nodules. The root nodules contained a high amount (16.9 microg/g fresh mass) of indole acetic acid (IAA). A big tryptophan pool (1555.1 microg/g fresh mass) was found in the root nodules, which might serve as a source of IAA production. The presence of IAA-metabolizing enzymes IAA oxidase and peroxidase indicated metabolism of IAA in the root nodules. The symbiont isolated from the root nodules of R. regia, a Rhizobium sp., produced high amount of IAA in culture when supplemented with tryptophan. The possible role of this IAA production in the monocotyledonous tree-Rhizobium symbiosis is discussed.

Developments in liquid membrane separation of beta-lactam antibiotics.

This paper presents an overview on the developments in liquid membrane separation and purification of commercially important beta-lactam antibiotics. Reactive extraction via liquid-liquid ion exchange or ion-pair extraction mechanism can be exploited to develop liquid membrane processes for separation and concentration of penicillins and cephalosporins. Because of high selectivity and flux, liquid membrane processes can be adopted for direct extraction of beta-lactams from fermentation broth. Other advantages of liquid membrane technologies are low capital and operating costs, compact unit installation in commercial plants, low material inventory, etc. Both emulsion liquid membrane and supported liquid membrane techniques can be effective under the reactive extraction conditions. However, the stability problems of liquid membrane should be resolved before commercial application can be established. Alternately, reactive extraction in non-dispersive mode with hollow fiber membranes can be an attractive and viable strategy for practical application. Applicability of the liquid membrane processes has been discussed from process engineering and design considerations.

Effect of transplanting time on incidence of alternataria leaf blight in solanum khasianum clark.

Solanum khasi Clark is a shrub which yields solasodine, a steroidal alkaloid. Transplating of seedlings of S. khasianum during November was found to be favourable for development of Alternaria leaf blight followed by transplanting in December, January and February. This paper presents the findings of the investigation.

Extraction and purification of cephalosporin antibiotics.

The biologically active natural and semisynthetic cephalosporin antibiotics require proper methods of extraction and purification for their isolation and subsequent pharmacological studies. This article reviews the various methods useful for extraction and purification of individual compounds as well as the enzymes involved in their biosynthesis. Applicability of the methods for downstream processing of the spent medium has been critically analysed. Adsorption chromatography, particularly with reverse phase materials, in combination with membrane separation is the most successful technique for extraction as well as purification of most of the enzymes and individual compounds. Techniques such as reactive extraction in liquid membrane, non-dispersive extraction in hollow fiber membrane and aqueous two-phase extraction are likely to emerge in new generation processes. Finally, some aspects of process design and scale-up have been discussed, highlighting the research needs of pragmatic importance.

A severe necrotic enterotoxin produced by certain food, food poisoning and other clinical isolates of Bacillus cereus.

The ability of certain strains of Bacillus cereus consistently to elaborate a filterable non-dialysable toxin capable of causing severe disruption and necrosis of the intestinal mucosa and submucosa is confirmed. This property is not universal to all B. cereus strains and different degrees of production of this toxin are exhibited by the different strains which produce it. The necrotic effect is produced by whole-cell cultures of the toxin producing strains in broth and in boiled rice. Some characteristics of this necrotic toxin are described and its relationship with the diarrhoeal and other known B. cereus toxins is discussed.

Multiple antibiotic resistance (MAR) index and its reversion in Pseudomonas aeruginosa.

The MAR indexes of hospital isolates of Pseudomonas aeruginosa were determined with reference to nine different cephalosporins. The values for all the strains were higher than 0.2 suggesting their origin from a high risk source of contamination where antibiotics are often used. Emergence of MAR pathogenic strains of Ps. aeruginosa indicated possible nosocomial infection in the hospital environment. beta-Lactamases produced by these organisms were tested and their inhibition by clavulanic acid was studied. beta-Lactamase produced by one of these strains (Ps-1) could not be inhibited by clavulanic acid whereas beta-lactamases of three other strains (Ps-2, Ps-3 and Ps-4) could be inhibited by clavulanic acid in the presence of cephalosporins, suggesting a possible use of clavulanic acid in combination with cephalosporins, to combat beta-lactamase induced resistance in Ps. aeruginosa.

Steroid transformation by mutants of Mycobacterium sp. with altered response to antibiotics.

Mycobacterium sp. NRRLB3683 which is capable to convert beta-sitosterol to 1,4-androstadiene-3,17-dione (ADD) was treated with methyl methane sulfonate and two strains with altered sensitivity to various antibiotics were obtained. One of the strain was steroid 1(2)-dehydrogenase negative and the other positive. Efficiency of utilization of sterols followed the order beta-sitosterol > cholesterol > soluble cholesterol. The steroid 1(2)-dehydrogenase negative strain was capable of producing 17KS (AD) from beta-sitosterol and converting AD to testosterone and ADD to AD suggesting the negative role of 1(2)-dehydrogenase in sterol side chain cleavage and decrease in hydrogenase activity by mutation. But this enzyme can perform the reverse reaction under aerobic condition.

Salmonellas on pig farms and in abattoirs.

Salmonella infection on two pig farms and its relation to infection in pigs at slaughter was studied. On the first farm feed ingredients were mixed on the farm, and these included fish meal which was found to be contaminated with salmonellas. The feed was pumped to pigs in liquid form. There was a high salmonella isolation rate at slaughter when the contaminated fish meal was fed in liquid feed, but it was significantly lower when no fish meal was fed to the pigs examined at slaughter. In some instances the same serotypes were found in fish meal and pig excreta on the farm and in caecal contents of the pigs at slaughter. No serotype was repeatedly isolated from any source and it appeared that the serotypes were not able to establish themselves in the pigs. It is concluded that infection found at slaughter originated on the farm where fish meal introduced and maintained infection. There was an opportunity for salmonellas to have multiplied in the liquid feed for several hours each day.On a second farm environmental conditions were similar, but feed was given in the form of ready-made pellets and nuts. Salmonellas were not isolated from the feed. At slaughter there was a significantly lower isolation rate than on the first farm.