Biomedical subjects

D J Chaplin

Publications and source records attributed to D J Chaplin.

148 records · Page 9Linked to original sources

PubMedDate not supplied

Enhancement of chlorambucil cytotoxicity by combination with flavone acetic acid in a murine tumour.

Previous studies using murine tumours have shown enhanced action of certain chemotherapeutic compounds when combined with agents that reduce tumour blood flow. In the majority of cases the compounds used were cytotoxic to the induced hypoxic cells but in this study we have investigated the relative importance of changes in tumour pH following blood flow reductions. The role of tumour pH was investigated by using combinations of the cytotoxic alkylating agent Chlorambucil (CHL) with the vascular occluding agent Flavone Acetic Acid (FAA). Chlorambucil is a weak acid (pKa = 3.7) and is concentrated within cells exposed to culture media at low pH or to the acidic microenvironment in vivo. In vitro incubations showed that greater cytotoxicity was obtained when cells were incubated at low pH and that the cytotoxicity was independent of the level of oxygenation at the time of the drug incubation. Combination of both CHL and FAA in vivo resulted in greater reductions in cell survival and growth delay than when either agent was given alone. Simultaneous administration of the two agents were very effective, potentially due to two factors; firstly, that the pH of the tumour changes during ischaemia and secondly, that the reduced blood flow potentially alters the pharmacokinetic distribution of CHL resulting in 'drug-trapping' within the tumour. Since the action of CHL is independent of the induced hypoxia which results from blood flow reduction it is suggested that the increased in vivo action is due in part to the changes in tumour pH.

Adenocarcinoma↗

PubMedDate not supplied

Enhancement of mitomycin-C cytotoxicity by combination with flavone acetic acid in a murine tumour.

The antitumour activity of a combination of Mitomycin C (MMC), a prototypical bioreductive agent, with the vascular occluding agent, flavone acetic acid (FAA), was examined in a murine tumour. Flavone acetic acid induced a long lived reduction of blood flow in the tumour thereby inducing hypoxia and cell death by ischaemia. Dose response curves for tumour cell survival and regrowth delay were constructed after each agent administered alone or when combined. The greatest antitumour effect was measured when the two agents were administered simultaneously. The reduced tumour perfusion induced by the combination was not lower than that for FAA alone indicating that the greater in vivo effect was not due to enhancement of the vascular occluding effect of the FAA. The role of the tumour microenvironment in determining the MMC cytotoxicity was examined using in vitro incubations of MMC under controlled oxygenation and pH. MMC cytotoxicity was increased in hypoxia (enhancement ratio = 2.0) and also when extracellular pH was reduced from 7.4 to 6.4 (enhancement ratio = 1.5). Since the microenvironmental consequences of induced ischaemia are reductions in both oxygenation and pH these parameters are probably responsible in large part for the enhancement of cytotoxicity observed when MMC and FAA are combined.

Adenocarcinoma↗

PubMedDate not supplied

Radiosensitizing effect of nicotinamide and carbogen combined in fractionated pions or x-rays in SCCVII tumors.

Well-known radiotherapeutic strategies for hypoxic cells include hypoxic radiosensitizers, heavy particles, and fractionated irradiation. This study attempted to obtain the ultimate effectiveness of these strategies by combining nicotinamide plus carbogen (N + C) as a hypoxic radiosensitizer with fractionated pions. In addition, the influence on the N + C effect of X-ray dose rate used as a reference radiation was evaluated. When SCCVII tumors in the dorsum of feet reached 50 mm3 in volume, they were irradiated with pions (0.2 Gy/min), the same dose rate (LDR; 0.2 Gy/min) X-rays, or high dose rate (HDR; 1.5 Gy/min) X-rays in 10 fractions over 11 days. Nicotinamide (0.5 mg/g) was administered i.p. one hour before irradiation, and normobaric carbogen (95% oxygen and 5% carbon dioxide) was breathed from 10 min before irradiation. The effect was evaluated by tumor growth time (TGT50) assay. The combination of N + C significantly enhanced the effect of 30 Gy LDR and 28 Gy HDR X-rays, with the effect corresponding to that of 39 Gy HDR X-rays: the enhancement ratios were 1.2 and 1.4, respectively. The effect of 20 Gy pions was equivalent to the effect of 33 Gy HDR X-rays (ratio of 1.65), or the effect of N + C combined with 28 Gy HDR X-rays. However, N + C did not enhance the effect of 20 Gy pions. This suggested that the fractionated pions had great biological effectiveness against hypoxic cells. In conclusion, N + C afforded no additional benefit with fractionated pions, but it was thought to be of value for fractionated X-rays, even in a dose rate of 0.2 Gy/min.

Administration, Inhalation↗

PubMedDate not supplied

Effects of novel and conventional anti-cancer agents on human endothelial permeability: influence of tumour secreted factors.

A number of anti-cancer agents have been implicated in vascular toxicity. The effects have been attributed to direct drug toxicity towards endothelium. Little attention has been focussed on the interaction between anticancer drugs, endothelial cells and tumour secreted factors. It is well known that tumours can secrete factors such as vascular permeability factor which do affect endothelial cells and could alter their response to the vascular effects of anticancer drugs. In the present study, we have examined, in vitro, the direct effects of vinblastine (VBL), 5-fluorouracil (5-FU), melphalan (L-PAM) and the novel tubulin inhibitor combretastatin A-1 (CBS) on endothelial permeability under normal and tumour simulated conditions. Monolayers of human umbilical vein endothelial cells (HUVEC) grown on membrane filters were incubated in drug in normal growth medium or medium conditioned by the human melanoma cell line, RPMI-7951 (TCM). VBL caused a rapid increase in permeability during the first 20 minutes, which was maintained for the duration of the experiment (120 minutes). The effect was not altered by TCM or restored to control levels when VBL was replaced by drug-free medium. Similarly, CBS caused a rapid increase in permeability; however, in contrast to VBL, this increase was enhanced by TCM. The changes induced by VBL and CBS were accompanied by contraction of the endothelial F-actin cytoskeleton. Neither L-PAM nor 5-FU altered the permeability of HUVEC monolayers. This study demonstrates that certain anti-cancer agents have a direct effect on endothelial cells, leading to an increase in the permeability of endothelial monolayers. Both VBL and CBS have vascular components in their mode of action which may lead to vascular collapse and tumour necrosis.

Antineoplastic Agents↗