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At least 1,261 records · Page 70Linked to original sources
PubMed1999

Reporter gene assays for algal-derived toxins.

We have modified the cell-based directed cytotoxicity assay for sodium channel and calcium channel active phycotoxins using a c-fos-luciferase reporter gene construct. In this report we describe the conceptual basis to the development of reporter gene assays for algal-derived toxins and summarize both published and unpublished data using this method. N2A mouse neuroblastoma cells, which express voltage-dependent sodium channels, were stably transfected with the reporter gene c-fos-luc, which contains the firefly luciferase gene under the transcriptional regulation of the human c-fos response element. The characteristics of the N2A reporter gene assay were determined by dose response with brevetoxin and ciguatoxin. Brevetoxin-1 and ciguatoxin-1 induced c-fos-luc with an EC50 of 4.6 and 3.0 ng ml(-1), respectively. Saxitoxin caused a concentration-dependent inhibition of brevetoxin-1 induction of c-fos-luc with an EC50 of 3.5 ng ml(-1). GH4C1 rat pituitary cells, which lack voltage-dependent sodium channels but express voltage-dependent calcium channels, were also stably transfected with the c-fos-luc. GH4C1 cells expressing c-fos-luciferase were responsive to maitotoxin (1 ng ml(-1)) and a putative toxin produced by Pfiesteria piscicida. Although reporter gene assays are not designed to replace existing detection methods used to measure toxin activity in seafood, they do provide a valuable means to screen algal cultures for toxin activity, to conduct assay-guided fractionation and to characterize pharmacologic properties of algal toxins.

Animals↗
PubMed2004

Identification of a novel box C/D snoRNA from mouse nucleolar cDNA library.

By construction and screen of mouse nucleolar cDNA library, a novel mammalian small nucleolar RNAs (snoRNA) was identified. The novel snoRNA, 70 nt in length, displays structural features typical of C/D box snoRNA family. The snoRNA possesses an 11-nt-long rRNA antisense element and is predicted to guide the 2'-O-methylation of mouse 28S rRNA at G4043, a site unknown so far to be modified in vertebrates. The comparison of functional element of snoRNA guides among eukaryotes reveals that the novel snoRNA is a mammalian counterpart of yeast snR38 despite highly divergent sequence between them. Mouse and human snR38 and other cognates in distant vertebrates were positively detected with slight length variability. As expected, the rRNA ribose-methylation site predicted by mouse snR38 was precisely mapped by specific-primer extension assay. Furthermore, our analyses show that mouse and human snR38 gene have multiple variants and are nested in the introns of different host genes with unknown function. Thus, snR38 is a phylogenetically conserved methylation guide but exhibits different genomic organization in eukaryotes.

Animals↗
PubMed2000

A genotypic analysis of patients receiving Zidovudine with either Lamivudine, Didanosine or Zalcitabine dual therapy using the LiPA point mutation assay to detect genotypic variation at codons 41, 69, 70, 74, 184 and 215.

BACKGROUND: The Murex-Innogenetics LiPA HIV-1 RT assay can be used to identify the presence of mutations of the reverse transcriptase gene at codons 41, 69, 70, 74, 184 and 215 of HIV-1, which have been shown to confer resistance to the nucleoside analogs Zidovudine (ZDV), Lamivudine (3TC), Didanosine (ddI) and Zalcitabine (ddC). The M184V mutation of the reverse transcriptase gene of HIV-1 has been associated with resistance to 3TC, ddC and ddI. This mutation has also been observed in patients receiving ZDV+ddC and ZDV+ddI. We used LiPA HIV-1 RT assay to identify the presence of either consensus methionine 184 or the mutant valine 184 with three groups of patients who were treated with ZDV/3TC, ZDV/ddI or ZDV/ddC combination therapy. OBJECTIVES: The aim of our study was to determine the viral genotype of patients who were considered to be failing therapy, by two ways: using sequencing and LiPA assays. In particular we were interested in establishing a possible correlation between these methods. STUDY DESIGN: The study group consisted of a consecutive series of 33 patients with a treatment failure, 18 of whom received ZDV+3TC therapy, seven received ZDV+ddI and eight received ZDV+ddC therapy. We also examined a small cohort of seven seroconverters. RESULTS: The M184V mutation was observed in 47.0% of patients receiving ZDV+3TC combination therapy but was not observed in either patient group receiving either ddI or ddC as co-therapy with ZDV. There was no evidence of the L74V mutation in our study group in either the ZDV/ddI or ZDV/ddC combination therapy group. We found the frequency of the K70R mutation to be higher in patients treated with ZDV/ddI (P=0.033) or ZDV/ddC (P=0.3) when compared with patients treated with ZDV/3TC. CONCLUSION: The LiPA assay allowed for the rapid detection of wild type and amino acid variations at key positions conferring resistance to the most used antiviral RT inhibitors. This represented a rapid, quite sensitive, and simple genotyping test. For these reasons the LiPA assay proved to be useful in studying genetic resistance in large screenings, when key RT mutations could be useful in guiding an effective HIV-1 suppressing regimen.

Anti-HIV Agents↗
PubMed1996

HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time.

A new mathematical model was used to analyze a detailed set of human immunodeficiency virus-type 1 (HIV-1) viral load data collected from five infected individuals after the administration of a potent inhibitor of HIV-1 protease. Productively infected cells were estimated to have, on average, a life-span of 2.2 days (half-life t 1/2 = 1.6 days), and plasma virions were estimated to have a mean life-span of 0.3 days (t 1/2 = 0.24 days). The estimated average total HIV-1 production was 10.3 x 10(9) virions per day, which is substantially greater than previous minimum estimates. The results also suggest that the minimum duration of the HIV-1 life cycle in vivo is 1.2 days on average, and that the average HIV-1 generation time--defined as the time from release of a virion until it infects another cell and causes the release of a new generation of viral particles--is 2.6 days. These findings on viral dynamics provide not only a kinetic picture of HIV-1 pathogenesis, but also theoretical principles to guide the development of treatment strategies.

Antiviral Agents↗
PubMed1998

A natural view of microbial biodiversity within hot spring cyanobacterial mat communities.

This review summarizes a decade of research in which we have used molecular methods, in conjunction with more traditional approaches, to study hot spring cyanobacterial mats as models for understanding principles of microbial community ecology. Molecular methods reveal that the composition of these communities is grossly oversimplified by microscopic and cultivation methods. For example, none of 31 unique 16S rRNA sequences detected in the Octopus Spring mat, Yellowstone National Park, matches that of any prokaryote previously cultivated from geothermal systems; 11 are contributed by genetically diverse cyanobacteria, even though a single cyanobacterial species was suspected based on morphologic and culture analysis. By studying the basis for the incongruity between culture and molecular samplings of community composition, we are beginning to cultivate isolates whose 16S rRNA sequences are readily detected. By placing the genetic diversity detected in context with the well-defined natural environmental gradients typical of hot spring mat systems, the relationship between gene and species diversity is clarified and ecological patterns of species occurrence emerge. By combining these ecological patterns with the evolutionary patterns inherently revealed by phylogenetic analysis of gene sequence data, we find that it may be possible to understand microbial biodiversity within these systems by using principles similar to those developed by evolutionary ecologists to understand biodiversity of larger species. We hope that such an approach guides microbial ecologists to a more realistic and predictive understanding of microbial species occurrence and responsiveness in both natural and disturbed habitats.

Bacteria↗
PubMed2006

Germ-plasm specification and germline development in the parthenogenetic pea aphid Acyrthosiphon pisum: Vasa and Nanos as markers.

The germarium, oocytes and embryos of the parthenogenetic viviparous pea aphid Acyrthosiphon pisum are contained within a single ovariole. This species provides an excellent model for studying how maternally-inherited germ plasm is specified and how it is transferred to primordial germ cells. Previous studies have shown that germ cells are first segregated at the embryonic posterior after formation of the blastoderm. We used two cross-reacting antibodies against the conserved germline markers Vasa and Nanos, which specifically identified these presumptive germ cells, to investigate whether germ cells were determined during early development. We observed randomly-distributed weak expression of Vasa signals in the developing oocyte but no localization in the oocyte segregated from the germarium. Localized Vasa was not apparent until it was detected at the posterior in the embryo undergoing the second nuclear division. Nanos, on the other hand, was localized to a nuage-like structure surrounding the nucleus in the developing and segregated oocytes. At the beginning of the oocyte maturation division, Nanos localization shifted to the posterior and could be identified in successive stages until it was incorporated into the germ cells. Taken together, our results suggest that germ plasm is specified in the developing oocyte and that Nanos is an earlier germline marker than Vasa. Germ cells stained for Vasa remained at a dorsal location in the egg during mid-development and then were guided into abdominal segments A1 to A6 during germ-band retraction. We infer that germ cells coalesce with segmented gonadal mesoderm during this period.

Animals↗
PubMed1998

Progression of HIV in haemophilia.

The recent elucidation of the life cycle and dynamics of the human immunodeficiency virus (HIV) and technological advances in development of the HIV RNA PCR assay for sensitive detection of viral load have revolutionized the diagnosis, management, and treatment of HIV infection. Beginning with initial infection, there is unremitting, high-level viral replication that persists throughout the course of HIV infection. The measure of the amount of virus present in plasma, HIV viral load, is the single most important predictor of HIV progression, the best indicator of immune system decline, and the best guide for initiating and monitoring antiviral treatment. Further, HIV viral load has become the new yardstick against which other markers, including CD4 number, age, chemokine receptor mutations, cytotoxic T-cell responses, and neutralizing antibody titers are assessed. For individuals with haemophilia, additional 'markers' may have significant impact on the outcome of HIV disease. Chronic factor concentrate treatment has led to transfusion-associated hepatitis, co-infection with hepatitis C (HCV), and chronic liver disease. The latter may become accelerated with HIV progression and may lead to hepatotoxicity with antiviral drug therapy. Chronic factor concentrate treatment has also been associated with immunosuppression, including both B- and T-cell immune defects. In HIV(+) haemophilic men, this immune deficit has led to lower CD4 counts with HIV progression and poorer CD4 response to antiviral drugs than in gay men. The underlying haemophilic bleeding tendency may result in significant haemorrhage with HIV-associated immune thrombocytopenia and with protease inhibitor antiretroviral therapy. Although AIDS is the leading cause of death in this group, the reduction in the size of the haemophilia population over the next two centuries is estimated to be small, and survival should improve as better antiviral therapeutics are identified.

Acquired Immunodeficiency Syndrome↗
PubMed2005

[Interruption of antiretroviral therapy in chronically HIV-infected patients].

BACKGROUND AND OBJECTIVE: To describe the immunological, virological and clinical outcomes of HIV-infected patients who stop antiretroviral therapy (ART) and to identify the factors related to durability. PATIENTS AND METHOD: Retrospective study of patients who interrupt therapy after six months without clinical events, level of CD4+ > or = 500 cells/microl and HIV RNA > or = 5,000 copies/ml (3.7 log10). RESULTS: In October 2004, 44 patients were included, 32 (72%) of them were stables after one year of ART cessation (group A) and 12 (28%) patients had to restart therapy due to a decreased CD4+ count < 300 cells/microl (group B). Both groups were compared. CD4 cell count nadir (414 cells/microl [199] versus 171 cells/microl [107]; p = 0.000) and CD4+ count level at time of ART stop (920 [302] cells/microl versus 633 cells/microl [177] p = 0.004) showed differences with statistical significance. The most important CD4+ count fall was observed at third month after stopping ART; 588 cells/microl (288) on group A and 382 cells/microl (167) on group B. The mean time without ART was 27 months on group A and 7 months on group B. Two patients had acute retroviral syndrome, and one had Pneumocystis jiroveci pneumonia. Cholesterol levels were 199 mg/dl (42) and triglycerides 257 mg/dl (271) on ART and during interruption decreased to 155 (38) and 165 (122) mg/dl respectively. After multivariate analysis, a CD4+ count nadir > 200 cells/microl (p = 0,0005; OR = 0,12; 95% CI, 0.036-0,398) and a CD4+ count at time of ART stop > 800 cells/microl (p = 0,04; OR: 0,11; CI 95%: 0,015-0,936) were independently related to durability of therapy interruption. CONCLUSIONS: Prolonged discontinuation of ART guided by CD4+ response causes a low morbi-mortality. The cell count CD4+ nadir and the CD4+ count at time of ART cessation are protective factors of durability. An improvement of metabolic parameters is observed during the discontinuation of ART.

Adult↗
PubMed1999

The design and synthesis of potent inhibitors of hepatitis C virus NS3-4A proteinase.

Hepatitis C virus (HCV) is the cause of the majority of transfusion-associated hepatitis and a significant proportion of community-acquired hepatitis worldwide. Infection by HCV frequently leads to persistent infections that result in a range of clinical conditions including an asymptomatic carrier state, severe chronic active hepatitis, cirrhosis and, in some cases, hepatocellular carcinoma. The HCV genome consists of a single-stranded, positive sense RNA containing an open reading frame of approximately 9060 nucleotides. This is translated into a single polyprotein of approximately 3020 amino acids (C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B), which in turn is processed by a series of host and viral proteinases into at least 10 cleavage products. The N-terminal portion of the NS3 protein encodes a serine proteinase that is responsible for the cleavage at the NS3-4A, NS4A-4B, NS4B-5A and NS5A-5B junctions. The 54 amino acid NS4A protein is a cofactor that binds to the NS3 protein and enhances its proteolytic activity. This report describes the expression of a recombinant NS3-4A proteinase fusion protein in Escherichia coli and the in vitro characterization of the enzyme activity using synthetic peptide substrates. It then demonstrates how these results were employed to guide the design of potent inhibitors of this enzyme.

Amino Acid Sequence↗
PubMed2001

Isolation and characterization of fibroblasts derived from regenerating human periodontal defects.

In an attempt to understand better the cells responsible for periodontal regeneration, cells from human gingiva, periodontal ligament and regenerating periodontal defects treated with expanded polytetrafluorethylene membranes were isolated, cultured and characterized. Guided tissue regeneration procedures were carried out on three human volunteers around molar teeth destined for extraction. After a 6-week 'healing phase', fibroblast cell cultures were established from explants of the regenerating soft connective tissue (RTF), as well as from the associated periodontal ligament (PLF) and gingiva (GF). Following stimulation with platelet-derived growth factor-beta (PDGF) and insulin-like growth factor-1 (IGF-1), [3H]thymidine-uptake and dye-binding assays were used to assess the rate of DNA synthesis and cell proliferation, respectively. Northern blotting was used to measure the expression of mRNA for the extracellular matrix proteoglycans decorin, biglycan and versican. The results show that the GF and RTF proliferated more quickly than the PLF. PDGF and IGF-1 were mitogenic for all three cell types. Decorin mRNA expression was stronger in the GF than the RTF and PLF, whereas versican mRNA expression was stronger in the GF and PLF than the RTF. Biglycan mRNA expression was strong in the PLF, moderate in the GF and weak in the RTF. The growth factors did not affect the mRNA expression for biglycan, but they upregulated versican and downregulated decorin mRNA. It can be concluded that RTF exhibits properties characteristic of a reparative phenotype. More specifically, it proliferates faster than PLF, from which it is derived, while exhibiting a unique pattern of proteoglycan mRNA expression. Therefore, this study demonstrates that fibroblasts obtained from the regenerating periodontal defects exhibit characteristics consistent with their ability to facilitate periodontal regeneration.

Adult↗
PubMed2006

Short RNAs in environmental adaptation.

Non-coding small RNAs (19-24 nucleotide long) have recently been recognized as the important regulator of gene expression in both plants and animals. Several classes of endogenous short RNAs have partial or near perfect complementarity to mRNAs and a protein complex is guided by short RNAs to target mRNAs. The targeted mRNA is either cleaved or its translation is suppressed. Initially, short RNAs were believed to primarily regulate the normal development of plants and animals, but recent advances implicate short RNAs in environmental adaptation.

Acclimatization↗
PubMed1989

Regulation of cell adhesion receptors by transforming growth factor-beta. Concomitant regulation of integrins that share a common beta 1 subunit.

Cell adhesion to extracellular matrices is mediated by a set of heterodimeric cell surface receptors called integrins that might be the subject of regulation by growth and differentiation factors. We have examined the effect of transforming growth factor-beta 1 (TGF-beta 1) on the expression of the very late antigens or alpha beta 1 group of integrins in human cell lines. The six known members of this family share a common beta 1 subunit but have distinct alpha subunits that confer selective affinity toward type I collagen, fibronectin, laminin, and other as yet unknown cell adhesion proteins. Using a panel of specific antibodies and cDNA probes, we show that in WI-38 lung fibroblasts TGF-beta 1 elevates concomitantly the expression of alpha 1, alpha 2, alpha 3, alpha 5, and beta 1 integrin subunits at the protein and/or mRNA level, their assembly into the corresponding alpha beta 1 complexes, and their exposure on the cell surface. The rate of synthesis of total alpha subunits relative to beta 1 subunit is higher in TGF-beta 1-treated cells than in control cells. The characteristically slow (t1/2 approximately 10 h) rate of beta 1 conversion from precursor form to mature glycoprotein in untreated cells increases markedly (to t1/2 approximately 3 h) in response to TGF-beta 1. The results suggest that in WI-38 fibroblasts the beta 1 subunit is synthesized in excess over alpha subunits, and assembly of beta 1 subunits with rate-limiting alpha subunits is required for transit through the Golgi and exposure of alpha beta 1 complex on the cell surface. TGF-beta 1 does not induce the synthesis of integrin subunits that are not expressed in unstimulated cells, such as alpha 4 and alpha 6 subunits in WI-38 fibroblasts. However, alpha 4 and alpha 6 subunits can be regulated by TGF-beta in those cells that express them. The results suggest that TGF-beta regulates the expression of individual integrin subunits by parallel but independent mechanisms. By modifying the balance of individual alpha beta 1 integrins, TGF-beta 1 might modulate those aspects of cell migration, positioning, and development that are guided by adhesion to extracellular matrices.

Acetylglucosaminidase↗
PubMed2003

The tyranny of adenosine recognition among RNA aptamers to coenzyme A.

BACKGROUND: Understanding the diversity of interactions between RNA aptamers and nucleotide cofactors promises both to facilitate the design of new RNA enzymes that utilize these cofactors and to constrain models of RNA World evolution. In previous work, we isolated six pools of high affinity RNA aptamers to coenzyme A (CoA), the principle cofactor in biological acyltransfer reactions. Interpretation of the evolutionary significance of those results was made difficult by the fact that the affinity resin attachment strongly influenced the outcome of those selections. Here we describe the selection of four new pools isolated on a disulfide-linked CoA affinity matrix to minimize context-dependent recognition imposed by the attachment to the solid support. RESULTS: The four new aptamer libraries show no sequence or structural relation to a previously dominant CoA-binding species, even though they were isolated from the same initial random libraries. Recognition appears to be limited to the adenosine portion of the CoA--in particular the Höogsteen edge--for most isolates surveyed, even when a counter selection was employed to remove such RNAs. Two of the recovered isolates are eluted with intact CoA more efficiently than with AMP alone suggesting a possible pantotheine interaction. However, a detailed examination of recognition specificity revealed that the 3' phosphate of CoA, and not the pantotheine arm, determined recognition by these two isolates. CONCLUSION: Most aptamers that have been targeted towards cofactors containing adenosine recognize only the adenosine portion of the cofactor. They do not distinguish substituents on the 5' carbon, even when those substituents have offered hydrogen bonding opportunities and the selection conditions discouraged adenosine recognition. Beyond hydrogen bonding, additional factors that guide the selection towards adenosine recognition include aromatic stacking interactions and relatively few rotational degrees of freedom. In the present work, a sterically accessible, disulfide-linked CoA affinity resin afforded the selection of a more diverse aptamer collection then previous work with a N6 linked CoA resin.

Adenosine↗
PubMed2002

Phosphates, DNA, and the search for nonterrean life: a second generation model for genetic molecules.

Phosphate groups are found and used widely in biological chemistry. We have asked whether phosphate groups are likely to be important to the functioning of genetic molecules, including DNA and RNA. From observations made on synthetic analogs of DNA and RNA where the phosphates are replaced by nonanionic linking groups, we infer a set of rules that highlight the importance of the phosphodiester backbone for the proper functioning of DNA as a genetic molecule. The polyanionic backbone appears to give DNA the capability of replication following simple rules, and evolving. The polyanionic nature of the backbone appears to be critical to prevent the single strands from folding, permitting them to act as templates, guiding the interaction between two strands to form a duplex in a way that permits simple rules to guide the molecular recognition event, and buffering the sensitivity of its physicochemical properties to changes in sequence. We argue that the feature of a polyelectrolyte (polyanion or polycation) may be required for a "self-sustaining chemical system capable of Darwinian evolution." The polyelectrolyte structure therefore may be a universal signature of life, regardless of its genesis, and unique to living forms as well.

DNA↗
PubMed1998

Differential gene expression in Arabidopsis monitored using cDNA arrays.

Large numbers of genes are being discovered on a daily basis for a variety of organisms including Arabidopsis thaliana. To obtain more functional information on these genes, efficient expression monitoring methods need to be developed. In this report we studied the steady-state mRNA levels of over 800 Arabidopsis genes in parallel using high-density arrays of partially sequenced cDNA. The technology is simple and robust and reliably permits the detection of down to twofold variation in mRNA levels. The detection limit lies below 0.01% of the total mRNA population. The comparison of the profiles obtained for light-grown and dark-grown seedlings revealed significant variations in mRNA levels for about 16% of the cDNA investigated. This technology not only provides new functional information on anonymous genes, and thus may guide reverse-genetics approaches, but also constitutes a powerful tool for global gene expression studies, with many potential applications in plant biology.

Arabidopsis↗
PubMed2007

Time trends for HIV-1 antiretroviral resistance among antiretroviral-experienced and naive pregnant women in New York City during 1991 to early 2001.

Time trends in the prevalence of drug resistance to antiretroviral therapy (ART) in pregnant women have not been studied. Treatment and prophylactic efficacy could be compromised by drug-resistant HIV strains. We conducted a repeated cross-sectional study of antiretroviral resistance mutations to nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) and of major mutations to protease inhibitors (PIs) in virus isolates from 300 HIV-infected pregnant women in New York City from 1991 to early 2001. The overall prevalence of mutations for NRTIs from 1991 to early 2001 was higher for ART-experienced (25.6% [95% confidence interval (CI): 19.1% to 32.1%]) than ART-naive (8.6% [95% CI: 3.7% to 13.4%]) mothers (P < 0.002). For NNRTIs, the overall prevalence of mutations was somewhat higher among ART-experienced (5.8% [95% CI: 2.3% to 9.3%]) versus ART-naive (1.6% [95% CI: 0% to 3.7%]) women (P = 0.06), and increased over time for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-19.4%; P = 0.0002). The prevalence of PI-associated mutations was also higher overall among ART-experienced mothers (5.8% [95% CI: 2.3% to 9.3%] vs. 1.6% [95% CI: 0% to 3.7%]; P = 0.06), with increases over time seen for ART-naive women (0%-7.4%; P = 0.03) and ART-experienced women (0%-16.1%; P = 0.0008). The increasing prevalence of drug resistance in pregnant women, including those who are drug-naive, underscores the necessity for resistance testing to guide treatment to achieve suppression of the mother's virus.

Adult↗
PubMed1998

Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.

To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-alpha-2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 10(12) virions per day. The estimated infected cell death rate exhibited large interpatient variation (corresponding t1/2 = 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.

Alanine Transaminase↗
PubMed1975

Review of basic concepts of cell kinetics as applied to brain tumors.

The authors review and discuss the basic concepts of cell kinetics as applied to brain tumors. Uncontrolled growth of a neoplasm represents an expanding tumor cell population. Four growth parameters characterize the behavior of a neoplastic population: cell cycle time, growth fraction, tumor doubling time, and cell loss. The concept of provisionally nondividing cells explains the disparity between cell cycle time and tumor doubling time. Human gliomas, like many non-neural solid tumors, contain variable proportions of actively proliferating and nonproliferating tumor cells; this ratio is expressed by the growth fraction. The major kinetic difference between glioblastomas and differentiated astrocytomas resides in their respective growth fractions, in all likelihood an inherent biological characteristic of each tumor. Glioblastoma proliferates at a rapid rate, and only a high rate of cell loss prevents this tumor from doubling its volume in less than 1 week. The selection of drugs and design of drug schedules for treatment of glioblastomas should be made with the knowledge that 60% to 70% of the cells in this tumor are resting (nonproliferating). If experience with other solid tumors is any guide, judicious selection and combined use of drugs according to kinetically sound schedules will produce more effective chemotherapy of brain tumors.

Alkylating Agents↗