Martin H.N. Tattersall

A randomized study: Small cell anaplastic lung cancer treated by combination chemotherapy and adjuvant radiotherapy

Chemotherapy and primary site radiation therapy were compared to chemotherapy alone in a randomized study of 125 patients with small cell cancer of the lung. The sites of initial relapse, as well as disease free and overall survival were analyzed. Radiotherapy to the primary site reduced the rate of local relapse, but median survival was not prolonged in patients with either limited or extensive disease, when the radiation therapy-chemotherapy group was compared to the group that received chemotherapy alone.

Metastatic adenocarcinoma of unknown primary site: a randomized study of two combination chemotherapy regimens

Of 101 patients with symptomatic adenocarcinoma or undifferentiated carcinoma of unknown primary site, 95 were evaluable for the effects of two randomized chemotherapy regimens. Forty-eight patients received combination doxorubicin and mitomycin C (DM) and 47 received combination cisplatin, vinblastine and bleomycin (PB). Response rates were not significantly different between the two treatment groups, 42% for DM and 32% for PVB, with an overall response rate of 37.1%. Survival differences for DM and PVB treated groups were not significantly different, with 18 weeks and 25 weeks median survivals respectively. Toxicities were unequal for the two treatment groups with increased haematological toxicity for DM and greater gastrointestinal toxicity for PVB. The authors conclude both therapies were of limited efficacy in the treatment of ACUP patients and emphasize that only symptomatic patients should be considered for such therapies.

Combination chemotherapy followed by surgery or radiotherapy in patients with locally advanced cervical cancer

Forty‐seven patients with locally advanced cervical cancer at high risk of relapse received three cycles of chemotherapy with PVB (cisplatin, vinblastine and bleomycin) before definitive local treatment with either radical surgery or radiotherapy. Thirty‐one of the 47 patients (66%) responded to initial chemotherapy, and 11 of them have relapsed compared with 13 of the 16 non‐responders. Median time to recurrence was 31 weeks for PVB non‐responders but has not yet been reached for PVB responders. After a median follow‐up of 128 weeks, 14 of the 31 responders (45 %) are alive and disease free compared with 3 of the 16 non‐responders (19%). There was a positive correlation between response to chemotherapy and subsequent response to radiotherapy. PVB was in general well tolerated although one death is probably attributable to chemotherapy. A randomized study comparing radiotherapy alone with initial PVB chemotherapy followed by radiotherapy is in progress.

Proteolipid identified by magnetic resonance spectroscopy in plasma of a patient with borderline ovarian tumour

Magnetic resonance spectroscopy (MRS) can identify abnormal lipoproteins in the plasma of patients with premalignant and malignant tumours. Proteolipid complexes, 8-11 nm and 25-28 nm in size, were isolated from the plasma of a patient with a borderline ovarian tumour. These complexes, which generated a characteristically long MRS T2 relaxation value (greater than 400 ms), were disrupted by ribonuclease. None of the conventional lipoproteins had a T2 value above 160 ms. Chemical analysis of the proteolipid complexes showed a 20% glycolipid component, and MRS identified a fucosylated molecule as the origin of the long T2 value. 9 months after resection of all tumour, a visible lipoprotein band, possibly lipoprotein (a), persisted in the plasma but neither the long T2 relaxation value nor the 8-11 nm or 25-28 nm particles were present. The long T2 relaxation value in the MRS profile, found in isolated proteolipid and unfractionated plasma and serum of other patients with carcinoma of the ovary and colon, provides a non-invasive method of assaying for cancer.

The activities of thymidine metabolising enzymes during the cell cycle of a human lymphocyte cell line LAZ-007 synchronised by centrifugal elutriation.

The activities throughout the cell cycle of thymidine kinase (EC 2.7.1.21), dihydrothymine dehydrogenase (EC 1.3.1.2), thymidine phosphorylase (EC 2.4.2.4) and dTMP phosphatase (EC 3.3.3.35) were measured in the Epstein-Barr virally transformed human B lymphocyte line LAZ-007. Cells were synchronised at different stages of the cell cycle using the technique of centrifugal elutriation. The degree of synchrony in each cycle-stage cell population was determined by flow microfluorimetric analysis of DNA content and by measurement of thymidine incorporation into DNA. The activity of the anabolic enzyme thymidine kinase was low in the G1 phase cells, but increased manyfold during the S and G2 phases, reaching a maximum after the peak of DNA synthesis, then decreasing in late G2 + M phase. By contrast, the specific activities of the enzymes involved in thymidine and thymidylate catabolism, dihydrothymine dehydrogenase, thymidine phosphorylase and dTMP phosphatase remained essentially constant throughout the cell cycle, indicating that the fate of thymidine at different stages of the cell cycle is governed primarily by regulation of the level of the anabolic enzyme thymidine kinase and not by regulation of the levels of thymidine catabolising enzymes.

Cytogenetic findings in cell lines derived from four ovarian carcinomas

Six cell lines, established from four primary ovarian carcinomas were examined cytogenetically. The lines varied greatly in their chromosome complement. All cells from the lines were aneuploid, although one cell line contained two populations having a pseudodiploid and a pseudotetraploid modal chromosome number. Every chromosome group was involved with loss and gain of chromosomes, but some individual chromosomes were more prone to aneuploidy than others. Chromosome #6 was the most stable throughout. Structural changes gave rise to many marker chromosomes. Although most markers were random and the majority unidentifiable, some abnormalities of clonal origin were found. Deletions especially of chromosome #1, were the most common change. Further sequential studies may elicit the origin, stability, and timing of the chromosome abnormalities.

Radioimmunoassays of plasma thymidine, uridine, deoxyuridine, and cytidine/deoxycytidine.

Abstract Radioimmunoassay techniques have been developed for the assay of thymidine, uridine, deoxyuridine, and deoxycytidine. Plasma levels of the first three nucleosides have been measured, and an upper limit has been determined for the plasma concentration of deoxycytidine. The assays involve displacement of a [ 3 H]pyrimidine nucleoside from the appropriate labeled rabbit immunoglobulin. By assaying a mixture of uridine and deoxyuridine in the presence and absence of borax, the concentrations of both nucleosides have been measured. In seven healthy adults, plasma levels of uridine were 21.1 ± 8.4 μ m (mean ± SD) and of deoxyuridine were 0.62 ± 0.39 μ m . In cancer patients, thymidine levels were 7.5 ± 2.7 × 10 −7 m . The upper limit for plasma deoxycytidine levels in six healthy adults was 0.71 ± 0.1 μ m .

The determination of purine levels in human and mouse plasma

Abstract The plasma concentration of the purines xanthine, hypoxanthine, inosine, adenosine, and guanosine have been measured in plasma from DBA mice and normal human volunteers. The assay system employed is based on the fluorimetric detection of H 2 O 2 produced via sequential catabolism of purine ribosides and purine bases to uric acid and uses commercially available enzyme preparations. Catabolic enzymes in vivo can rapidly alter the dynamic equilibrium of plasma purines once blood has been withdrawn; consequently, the use of inhibitors of purine catabolism in blood collection has major effects on purine recovery. The use of an adenosine deaminase inhibitor (erythro-9-(2-hydroxy-3-nonyl)adenine) during blood collection markedly influences purine profiles and ensures more accurate quantitation of in vivo plasma purine levels. The need for rapid separation of cellular elements after venepuncture is also demonstrated. In normal human plasma from five volunteers, average concentrations are hypoxanthine/xanthine, 0.7 μ m ; inosine, 0.2 μ m ; adenosine, 2.0 μ m ; and guanosine, undetectable. The average purine levels from DBA mice are hypoxanthine/xanthine, 2.9 μ m ; inosine, 2.3 μ m ; adenosine, 6.1 μ m ; and guanosine, undetectable.

Allopurinol modulation of fluorouracil toxicity

SummaryConsiderable interest has developed in the modulation of fluorouracil activity by nucleosides. The toxicity of fluorouracil in mice is known to be reduced by concurrent administration of allopurinol, presumably because biochemical pathways activating fluorouracil in normal tissues are blocked.We have given allopurinol (300 mg t.d.s. PO) concurrently with continuous infusions of fluorouracil (2.0–2.25 g/m2/day x 5) to 34 patients with colorectal cancer and 11 patients with various adenocarcinomas. There were 41 patients assessable for toxicity. Stomatitis was the predominant dose-limiting toxicity (22% grade 1, 19% grade 2, and 27% grade 3 toxicity). Neutropenia (<1,000/μl) occurred in 17% patients. Among 26 colorectal cancer patients assessable for response there was a 15.4% response rate.We conclude that allopurinol modulates fluorouracil toxicity in man, allowing a two-fold increase in dose. However, at least in colorectal cancer no greater frequency of tumour response is seen than with lower doses of fluorouracil given by standard schedules of administration without allopurinol.

Ribosomal RNA gene amplification: a selective advantage in tissue culture.

A CCRF-CEM (human T-cell leukemia) line, initially made resistant to methotrexate by a four-step increase in drug concentration, revealed a large marker of one chromosome #14 in all cells after a 6-month period of culture in the absence of drug. The marker is the result of a triple duplication of both the satellite and stalk. In situ hybridization with 3H-cRNA and NOR banding proved that ribosomal DNA had been amplified and was actively transcribed. Flow cytometric analysis showed a significant increase of RNA versus DNA in G1 cells compared with those of the original drug-resistant parent. The abnormal chromosome appeared after the removal of methotrexate from culture and may be related to the faster doubling time of this line compared with the parent line.