Quality of life analyses from vinorelbine (Navelbine) clinical trials of women with metastatic breast cancer.

The effect of therapy on a patient's quality of life (QOL) is an important factor in choosing a treatment, especially when the primary intent of therapy is palliation of symptoms. An increasing recognition of the importance of QOL prompted inclusion of QOL assessments in a number of clinical trials of women with breast cancer. This report describes two clinical trials in which women with metastatic breast cancer were treated with intravenous (IV) vinorelbine (Navelbine; Burroughs Wellcome Co, Research Triangle Park, NC; Pierre Fabre Médicament, Paris, France). In a randomized trial, IV vinorelbine was compared with IV melphalan (Alkeran; Burroughs Wellcome Co) as second- or third-line treatment in patients with anthracycline-refractory breast cancer. In a second, nonrandomized study, vinorelbine was used as first- or second-line treatment in patients who had not received doxorubicin previously. Both studies assessed the QOL dimensions of physical functioning, symptom status, role functioning, and global QOL. In the randomized trial, analyses of linear time trends indicated that patients treated with vinorelbine compared with patients receiving IV melphalan had better physical functioning throughout most of the study. Differences between the two treatment groups in other QOL dimensions were not significant. In the nonrandomized study, patients who received vinorelbine as first-line therapy had worse role functioning and somewhat worse physical functioning than those who received the drug as second-line treatment. Overall, these studies suggest that patients who receive IV vinorelbine treatment maintain a reasonable QOL and that this agent is comparable to or better in some respects than IV melphalan.

Systemic gamma-interferon therapy for recurrent gliomas.

Recombinant gamma-interferon (2 mg/sq m) was administered intravenously twice weekly in 8-week courses to 14 patients with recurrent gliomas. Computerized tomography (CT) evidence of response was seen in only one patient, and stabilization for 12 to 86 weeks was recorded in three. This was a disappointing result, particularly in a series of patients with relatively small initial tumor volumes (less than 50 cu mm on enhanced CT) and Karnofsky functional ratings of 70 or higher. In addition, several instances of toxicity potentially attributable to gamma-interferon were observed.

Systemic beta-interferon therapy for recurrent gliomas: a brief report.

Recombinant beta-interferon in escalating dosages was administered intravenously three times weekly to seven patients with recurrent gliomas. No evidence of response was seen in any patient, either on neurological examination or by computerized tomography (CT). However, stabilization of tumor volume, assessed from contrast-enhanced CT scans, occurred for 8 to 26 weeks in three patients. Immediate progression of disease despite treatment occurred in four patients.

Intracarotid cisplatin chemotherapy for recurrent gliomas.

Forty patients with recurrent gliomas were treated with monthly intra-arterial infusions of cisplatin. Of the 35 evaluable patients, 12 (34%) responded with computerized tomography (CT) evidence of a decrease in tumor size; in 14 (40%) the tumor stabilized on CT scans, and in nine (26%) the disease progressed. The median survival period was 35.0 weeks for the responders and 27.5 weeks for all 35 patients. The primary toxicities were renal (reversible alterations in creatinine clearance), otological (severe hearing loss in one patient), and likely neurotoxicity in one patient who had received bilateral infusions following contralateral tumor progression. The authors are now using this form of regional chemotherapy sequentially before and following radiotherapy in newly diagnosed cases.

Randomized phase III trial of single versus multiple chemotherapeutic treatment following surgery and during radiotherapy for patients with anaplastic gliomas.

In 81 patients with anaplastic supratentorial gliomas, single versus multiple chemotherapeutic agents were selected for treatment following surgery and during radiotherapy in a prospective randomized study. Time to treatment failure and survival were not significantly enhanced by multiple agent chemotherapy, as administered in this study.

ATP utilization by rep protein in the catalytic separation of DNA strands at a replicating fork.

Hydrolysis of ATP by rep protein proceeds in the presence of a single-stranded region of DNA 4 residues long, but the true effector for rep ATPase appears to be a replicating fork rather than a random coil. At or near a fork in duplex DNA, rep ATPase action is different from what it is on DNA lacking secondary structure (single-stranded): (i) Km for ATP is lower, (ii) specificity is for ATP and dATP with no action on other nucleoside triphosphates, (iii) sensitivity to certain ATP analogs is reduced, (iv) presence of a DNA-nicking enzyme (e.g. cistron A protein induced by phiX174) is required, and (v) Escherichia coli DNA binding protein facilitates rather than inhibits. During the separation of strands accompanying replication, 2 molecules of nucleoside triphosphate (ATP or dATP) are hydrolyzed for every nucleotide polymerized. Utilization of ATP by rep protein may provide energy for catalytic strand separation at a fork in advance of replication.

The deoxyribonucleic acid unwinding protein of Escherichia coli. Properties and functions in replication.

The DNA unwinding protein of Escherichia coli (Sigal, N., Delius, H., Kornberg, T., Gefter, M., and Alberts, B. (1972) Proc. Nat. Acad. Sci. U.S.A. 69, 3537-3541) has been purified to homogeneity by a simple procedure which utilizes its stability to heating. The protein is an asymmetric tetramer of 18,500 dalton subunits which binds preferentially to single-stranded DNA at a ratio of one protein molecule per 32 nucleotides. Binding to DNA is complete in less than 10 s at 0 degrees while release of the protein from single-stranded DNA is relatively slow even at 37 degrees. A simple functional assay for unwinding protein depends on its essential role in the conversion of phage G4 single-stranded DNA to the replicative form. Unwinding protein stimulates initiation of replication of all single-stranded phage DNAs. Approximately 300 copies of unwinding protein are present per cell, as estimated by antibody titration, an amount sufficient to cover substantial lengths of DNA in several replicating forks.

Guanosine pentaphosphate phosphohydrolase of Escherichia coli is a long-chain exopolyphosphatase.

An exopolyphosphatase [exopoly(P)ase; EC 3.6.1.11] activity has recently been purified to homogeneity from a mutant strain of Escherichia coli which lacks the principal exopoly(P)ase. The second exopoly(P)ase has now been identified as guanosine pentaphosphate phosphohydrolase (GPP; EC 3.6.1.40) by three lines of evidence: (i) the sequences of five tryptic digestion fragments of the purified protein are found in the translated gppA gene, (ii) the size of the protein (100 kDa) agrees with published values for GPP, and (iii) the ratio of exopoly(P)ase activity to GPP activity remains constant throughout a 300-fold purification in the last steps of the procedure. The enzyme liberates orthophosphate by processive hydrolysis of the phosphoanyhydride bonds of polyphosphate [poly(P)] chains (1000 residues) or by hydrolysis of the 5'-gamma-phosphate of guanosine 5'-triphosphate 3'-diphosphate (pppGpp) to guanosine 5'-diphosphate 3'-diphosphate (ppGpp or "magic spot"). The Km for long-chain poly(P) as a substrate (approximately 0.5 nM) is far lower than that for pppGpp (0.13 mM); the kcat for the poly(P)ase activity is 1.1 s-1 and that for pppGpp hydrolase is 0.023 s-1. These and other findings direct attention to possible functions of poly(P) in the response of E. coli to stresses and deprivations.

Biochemical studies of bacterial sporulation and germination. XIV. Phospholipids in Bacillus megaterium.

The principal phospholipids of Bacillus megaterium throughout the cycle of growth and sporulation were found to be phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, and a hitherto unidentified isomer of glycosaminyl-phosphatidylglycerol. Phosphatidylglycerol predominated during vegetative cell growth and then declined as spores developed, whereas diphosphatidylglycerol became more prominent during spore maturation. The latter phosphatide was relatively inaccessible in the vegetative cell and was more accessible in the spore, as judged by solvent extraction under various conditions.

Central neurotoxicity following intracarotid BCNU chemotherapy for malignant gliomas.

Central neurotoxicity is reported in 5 of 16 patients with recently diagnosed anaplastic gliomas, who received intra-arterial BCNU (200 mg/M2/course) and also 2 in a series of 26 patients with recurrent gliomas similarly treated. Neurotoxicity was usually delayed, commencing several weeks following the second or third course. CT scans during central neurotoxicity represented 1 or more of 3 patterns: no change; increased low density area(s); and/or ipsilateral gyral enhancement and punctate calcification in the middle cerebral artery territory. In one clinicopathological correlation, coagulative necrosis of the white matter was observed, identical histologically to those changes recognized as delayed vascular events following radiotherapy. Cautious exploration of the various clinical factors that may contribute to this toxicity seems appropriate, as exploration of the potential benefits of regional chemotherapeutic infusions is undertaken.

A mechanism of duplex DNA replication revealed by enzymatic studies of phage phi X174: catalytic strand separation in advance of replication.

The enzyme system for duplicating the duplex, circular DNA of phage phi X174 (replicative form) in stage II of the replicative life cycle was shown to proceed in two steps: synthesis of the viral (+) strand ]stage II(+)], followed by synthesis of the complementary (-) strand ]stage II(-)] [Eisenberg et al. (1976) Proc. Natl. Acad. Sci. USA 73, 3151-3155]. Novel features of the mechanism of the stage II(+) reaction have now been observed. The product, synthesized in extensive net quantities, is a covalently closed, circular, single-stranded DNA. The supercoiled replicative form I template and three of the four required proteins--the phage-induced cistron A protein (cis A), the host rep protein (rep), and the DNA polymerase III holoenzyme (holoenzyme)--act catalytically; the Escherichia coli DNA unwinding (or binding) protein binds the product stoichiometrically. In a reaction uncoupled from replication, cis A, rep, DNA binding protein, ATP, and Mg2+ separate the supercoiled replicative form I into its component single strands coated with DNA binding protein. In the presence of Mg2+, cis A, nicks the replicative form I; rep, ATP, and Mg2+ achieve strand separation with a concurrent cleavage of ATP and binding of DNA binding protein to the single strands. rep exhibits a single-stranded DNA-dependent ATPase activity. These observations suggest that the rep enzymatically melts the duplex at the replicating fork, using energy provided by ATP; this mechanism may apply to the replication of the E. coli chromosome as well.

Initiation of DNA synthesis: synthesis of phiX174 replicative form requires RNA synthesis resistant to rifampicin.

Conversion of single-stranded DNA of phage varphiX174 to the double-stranded replicative form in Escherichia coli uses enzymes essential for initiation and replication of the host chromosome. These enzymes can now be purified by the assay that this phage system provides. The varphiX174 conversion is distinct from that of M13. The reaction requires different host enzymes and is resistant to rifampicin and streptolydigin, inhibitors of RNA polymerase. However, RNA synthesis is essential for varphiX174 DNA synthesis: the reaction is inhibited by low concentrations of actinomycin D, all four ribonucleoside triphosphates are required, and an average of one phosphodiester bond links DNA to RNA in the isolated double-stranded circles. Thus, we presume that, as in the case of M13, synthesis of a short RNA chain primes the synthesis of a replicative form by DNA polymerase. Initiation of DNA synthesis by RNA priming is a mechanism of wide significance.

Initiation of replication of the Escherichia coli chromosomal origin reconstituted with purified enzymes.

A mixture of purified proteins has replaced a crude enzyme fraction capable of efficient replication of oriC-containing plasmids. The reconstituted enzyme system contains proteins which provide initiation, replication, and specificity functions required for dnaA-dependent replication specific for an oriC template. Replication can be separated into successive stages of RNA synthesis and DNA replication. Isolation of an intermediate no longer requiring RNA polymerase action requires the presence of dnaA protein, DNA gyrase, dnaB protein and dnaC protein. Intermediate formation likely involves binding of dnaA protein to a 9-bp sequence present 4 times as inverted repeats within the chromosomal origin sequence.

Cerebral arterial spasm--a controlled trial of nimodipine in patients with subarachnoid hemorrhage.

We enrolled 125 neurologically normal patients with intracranial aneurysms in a multi-institution, prospective, double-blind, randomized, placebo-controlled trial within 96 hours of their subarachnoid hemorrhage, to determine whether treatment with the calcium blocker nimodipine would prevent or reduce the severity of ischemic neurologic deficits from arterial spasm. A deficit from cerebral arterial spasm that persisted and was severe or caused death by the end of the 21-day treatment period occurred in 8 of 60 patients given placebo and in 1 of 56 given nimodipine (P = 0.03, Fisher's exact test). Analysis of the amount of basal subarachnoid blood on pre-entry CAT scans in patients with deficits from spasm showed that an increase in subarachnoid blood was not associated with a worse neurologic outcome among patients who received nimodipine, unlike the situation in patients given a placebo. There were no side effects from nimodipine. We conclude that nimodipine should be given to patients who are neurologically normal after subarachnoid hemorrhage in order to reduce the occurrence of severe neurologic deficits due to cerebral arterial spasm.