Richard M. Fox

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.

Analysis of a prospectively randomized comparison of doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: implications for future studies.

A multi-institutional cooperative study of patients with locally advanced, recurrent, or metastatic gastric adenocarcinoma who had not previously received chemotherapy was conducted, prospectively randomizing patients to receive either doxorubicin or the three-drug combination, 5-fluorouracil (5-FU), doxorubicin (Adriamycin; Adria Laboratories, Columbus, Ohio), and BCNU (FAB). The 187 evaluable patients were initially stratified according to the presence of measurable or evaluable disease and performance status. There was a significantly higher response rate observed for FAB (40%) compared with doxorubicin (13%) among the 145 measurable-disease patients. Duration of response and survival were significantly longer for FAB in the measurable-disease group, but for the total patient population an early advantage for FAB in time to disease progression and survival was lost with continued follow-up. Median survival was 33 weeks for patients receiving FAB and 19 weeks for those receiving doxorubicin. Significant pretreatment factors adversely affecting survival included poor performance status, weight loss of greater than 10%, and more than two sites of metastases. Toxicity was not severe in either treatment arm, and only thrombocytopenia occurred significantly more often with FAB. It is contended that in the treatment of advanced gastric cancer, chemotherapy only exerts a relatively short-term and modest beneficial effect, most apparent in patients with intermediate tumor bulk. 5-FU remains the most active single agent, and combination chemotherapy has not yet proven its overall worth. Further studies are indicated comparing the most active combinations with 5-FU using optimal doses and schedules, and consideration must be given to the incorporation of no-treatment controls.

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.

Lipid domain in cancer cell plasma membrane shown by 1H NMR to be similar to a lipoprotein

Human blood lipoproteins have been characterised by 1H NMR methods and chemical analysis, and comparisons made with the properties of the triglyceride‐rich plasma membrane domain found in cancer cells. By means of selective and non‐selective T 1 experiments, the lipids in HDL and LDL are shown to be in diffusive exchange. In contrast, the lipids ofchylomicra and VLDL do not exhibit lipid diffusion, and therefore resemble the neutral lipids of cancer cell plasma membranes. 2D scalar correlated NMR (COSY) spectra of cancer cells or solid tumours are similar to those obtained from VLDL and LDL. The long T 2 relaxation value observed for neutral lipid methylenes in metastatic cancer cells (>00 ms) was not observed for any of the 4 lipoproteins studied. None of the lipoprotein classes gave a T 2 longer than 250 ms.

Combination therapy with methotrexate and 5-fluorouracil: a prospective randomized clinical trial of order of administration.

Because of biochemical and tissue culture evidence casting doubt on the physiologic relevance of reported synergy afforded by sequential administration of methotrexate (MTX) followed by 5-fluorouracil (5-FU), a randomized controlled clinical trial was conducted in 108 patients with advanced cancer, including 70 with squamous cell carcinoma (SCC) of the head and neck, nine with SCC of other primary sites, 24 with colorectal, and five with gastric adenocarcinomas. Patients were randomized to receive weekly therapy consisting of MTX followed one hour later by 5-FU, or 5-FU followed one hour later by MTX. There was a trend to higher tumor response rates in patients treated with MTX before 5-FU (45% v 33% overall; 65% v 39% in patients with previously untreated head and neck cancer), but these differences were not significant, either by chi-square test or by multivariate stepwise logistic regression. The trend in survival favoring the reverse sequence of 5-FU before MTX was not significant in univariate analyses. Stepwise multivariate Cox model analysis showed that Eastern Cooperative Oncology Group performance status at study entry was the major prognostic factor for survival (P less than 0.001), but among the 70 patients with head and neck cancer, the sequence of drug administration was the only other significant prognostic factor for survival, and favored the sequence of 5-FU followed by MTX (P less than 0.025).

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.

Purinogenic lymphocytotoxicity: clues to a wider chemotherapeutic potential for the adenosine deaminase inhibitors.

Introduction ( d eoxy ) AT P t Inherited deficiencies of the purine catabolic enzymes aden6 4 (deoxy) ADP osine deaminase (ADA) and PNP produce selective accumu& / lation of purine deoxynucleotides in lymphocytes, resulting in l immunodeficiency disease in children. The finding that resting (deo×y)• tAMP lymphocytes are as susceptible to accumulated dATP as their 5 -1 ~ @ dividing precursors has extended the potential clinical role for NH2 the A D A inhibitor deoxycoformycin to include immunosupN / . J . J ~ / N × pressive therapy, modification of graft-versus-host disease, and the possible treatment of human lymphoid cancers. Attempts to account for purinogenic lymphocytotoxicity and H0CHz,0, I the special selectivity of this toxicity towards cultured T lymphoblasts have revealed some differences between lymphocyte subpopulations in their purine metabolic pathways, OH tOHl

A Rapid High-Performance Liquid Chromatographic Method for Quantitation of 5-Fluorouracil in Plasma after Continuous Intravenous Infusion

A fast, simple, precise, high-performance liquid chromatographic method for the assay of 5-fluorouracil in plasma from humans receiving continuous intravenous infusion is described. After a single extraction, underivatised 5-fluorouracil is assayed by high-performance liquid chromatography using a variable-wavelength ultraviolet detector. After extraction of 1 ml plasma, 0·3 μmol/l can be assayed. The assay is reproducible and linear up to at least 40 μmol/l. A single determination takes 3 hours and a batch of 40 specimens can be extracted and assayed in 4 working hours if automated equipment is used, enabling injections and calculations to be done overnight.

Four-drug combination chemotherapy for advanced cervical carcinoma

Thirty‐one patients with advanced stage squamous cell carcinoma of the cervix were treated with the four‐drug combination fluorouracil, doxorubicin, cyclophosphamide, and vincristine. Four patients achieved complete remission (13%) and 15 partial remission (45%). The only factor of adverse prognostic significance was poor initial patient performance. Median survival for the patients entering complete remission exceeded 54 weeks and was 43 weeks for patients achieving partial remission. Seven patients are still alive at 50 weeks. This represents a notable prolongation of survival compared with those patients who did not achieve remission. Toxicity for the combination was not excessive; myelosuppression and vincristine‐induced neuropathy were the most prominent. These results are moderately encouraging and confirm the sensitivity of cervical carcinoma to systemic chemotherapy. Further studies to define the optimal use of chemotherapy in both advanced and earlier stages of disease are warranted.