Bioprocessing of plant in vitro systems for the mass production of pharmaceutically important metabolites: paclitaxel and its derivatives.

Taxol (paclitaxel) and its derivatives are microtubule-stabilizing drugs widely used in the treatment of several types of cancer, including mammary, prostate, ovarian and non-small-cell lung carcinoma, as well as AIDS-associated Kaposi's sarcoma and other types of tumor. Taxanes stabilize microtubules by enhancing their polymerization and inhibiting depolymerization. Microtubule dynamics are crucial to mitotic spindle formation and function; therefore, cells exposed to taxanes are unable to undergo chromosomal separation during mitosis, become arrested in the G2/M phases of the cell cycle, and are subsequently targeted for apoptosis. Plant cell cultures are used for industrial-scale biotechnological production of important bioactive plant secondary metabolites, including the anticancer agent paclitaxel. In the last two decades, there have been numerous empirical approaches to improve the biotechnological production of taxanes, leading to the conclusion that treatment of Taxus sp. cells with methyl jasmonate or other elicitors is the most effective strategy. However, little insight has been gained into how the elicitors increase taxane biosynthesis or how this process is regulated. In recent years, with the help of "omics" tools, a rational approach has provided new information about taxane metabolism and its control. Once pathway bottlenecks have been identified, it will be possible to engineer Taxus sp. cell lines with overexpression of genes that control the flux-limiting steps, thus boosting taxane productivity. This review describes the chemical and biological characterization of paclitaxel and its derivatives and discusses future prospects for their biotechnological production.

Acute familial myositis with a common autoimmune response.

In 1986, we diagnosed and treated 4 patients, all members of 1 rural family, who presented simultaneously with a polymyositis-like syndrome, anticytoplasmic antibodies (on HEp-2 cells), and precipitating antibodies of anti-Jo-1 and anti-PM-Scl specificities. Serum samples from these patients reacted by immunodiffusion against serum from a rodent that had been caught in the patients' house. The precipitin line showed complete immunologic identity with anti-Jo-1. To study the specificity of this serum-serum reaction, 2 mice (Mus musculus) and 1 rat (Rattus rattus) from the neighboring areas of the patients' house were caught and killed. Sections of the liver, kidney, spleen, and skeletal muscle were processed for histopathologic examination and for direct and indirect immunofluorescence studies of the patients' sera. The rodents' sera were tested by immunodiffusion against serum samples from 25 patients with systemic lupus erythematosus, 11 with rheumatoid arthritis, 6 with mixed connective tissue disease, and 11 with various other rheumatic diseases, as well as 16 healthy controls. A serum-serum precipitin reaction was noted between the rodents' sera and sera from 2 of the patients with polymyositis-like syndrome. A distinct, but weaker, reaction was found with 2 lupus patients' sera (8%), and with 1 healthy control serum (6%). The rodents' sera were antinuclear antibody positive by indirect immunofluorescence on HEp-2 cells. These results, suggest that some rodents could be carriers of an as-yet-unknown transmissible agent that, in susceptible individuals, induces clinical and serologic manifestations similar to those of polymyositis.

Evidence of a new antigen-antibody system (anti-Mic-1) in patients with systemic lupus erythematosus and hyperthyroidism.

Autoimmune thyroid diseases may occur in association with systemic rheumatic disorders, and usually they show a high prevalence of antithyroglobulin and antimicrosomal antibodies. We report 6 patients with the clinical association of systemic lupus erythematosus (SLE) and hyperthyroidism. Of interest, in 5 of the 6 patients (83%), we found an antibody directed against a microsomal extract of human thyroid gland which was different than previous microsomal antibodies in that it was a precipitating antibody; we have called it anti-Mic-1 antibody. We investigated the prevalence of this specific autoimmune reaction in 58 patients with idiopathic SLE, 30 with hyperthyroidism, 15 with Hashimoto's thyroiditis, 25 with insulin dependent diabetes mellitus, 45 with rheumatoid arthritis, and 25 healthy controls. No control had anti-Mic-1 antibody. In addition, this antibody was shown to be organ specific. We suggest that patients with the combined association of SLE and hyperthyroidism may represent a different subset in the spectrum of SLE. The high prevalence of this antigen-antibody reaction in these cases may serve as a serological marker of this association.

Prevalence of antinuclear antibodies in patients with habitual abortion and in normal and toxemic pregnancies.

The prevalence of antinuclear antibodies (ANA) was investigated in the sera from patients with habitual abortion (HA) and in normal (NP) and toxemic pregnancies (TP). ANAs were more prevalent in patients with HA (30%) as compared with TP (15%) and the control group (6.6%). Only one patient, from the HA group, fulfilled four criteria for systemic lupus erythematosus (SLE). Most other patients with positive ANAs had some of the criteria for SLE, but none of the ANA negative patients had any of them. These studies suggest that there is a high prevalence of ANA in our group of women with HA and their identification may help to identify those patients who may eventually develop SLE which has been reported to be preceded in many women by repeated spontaneous abortions. In addition, immunological factors, at least in some cases, could play a role in the pathogenesis of HA.

Prevalence of anti-SSA (Ro) antibodies in a Mexican population of patients with various systemic rheumatic diseases.

The prevalence of anti-SSA (Ro) antibodies was investigated in 126 patients with various systemic rheumatic diseases and in 77 normal subjects. Also, we studied the relationship between these autoantibodies and the clinical features of our patients with SLE. Anti-SSA (Ro) occurred with a frequency of 14% in SLE but was not associated with specific clinical features of the disease. In Sjögren's syndrome the frequency was 25%, in rheumatoid arthritis 20.3% and in mixed connective tissue disease 15.4%. Finally, in the control group anti-SSA (Ro) antibodies were not present. We believe that the presence of this antibody is not specific to any rheumatic disease in our Mexican population, and should not be used as a "marker antibody" of some clinical features in patients with SLE.