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Single loop surface coil, often used in MR studies, was evaluated for its performance as an inductive hyperthermic applicator. The heat deposition pattern produced by the surface coil at 84 MHz and 34 MHz was mapped in muscle-mimicking agar phantoms. Temperatures were measured simultaneously at 64 points using multiple-junction thermocouples.

The pharmacokinetics of pentoxifylline and its three major metabolites were measured after intraperitoneal administration of 10 mg/g or 100 mg/kg of drug in C3H mice. Peak concentrations of pentoxifylline were approximately 10 and 100 micrograms/ml, respectively, with elimination half-lives (+/- 2 SE) of 4.6 (4.2-5.1) and 7.5 (7.2-7.9) min, respectively. Plasma concentrations of the pharmacologically active hydroxy metabolite were approximately one-tenth those of the parent compound. In vitro evidence of the ability of pentoxifylline to increase blood cell deformability indicates that concentrations of up to 30 micrograms/ml can increase deformability of both red and white blood cells; doses between 5 mg/kg and 100 mg/kg were therefore tested 15 min after administration to test the effect of the drug on tumour and normal tissue perfusion, tumour radiosensitivity and renal function immediately after exposure to appropriate drug concentrations. Using 86Rb extraction, doses of 10-100 mg/kg pentoxifylline were shown to increase relative tumour perfusion of the RIF-1 tumour to 140-170% of control, with no effect in skin, muscle, kidney, liver or lung, but with similar increases in spleen perfusion; there was no significant effect in any tissue after 5 mg/kg. Using a clonogenic assay, this increased tumour perfusion was shown to be reflected in increased tumour radiosensitivity to 25 Gy 15 min after pentoxifylline, with the same dose threshold of 10 mg/kg, and similar lack of dose-dependence at higher doses; the response indicated reduction in hypoxic fraction by a factor of 2-3. Renal function, measured by [51Cr]EDTA and [125I]iodohippurate clearance was unaffected at doses up to 50 mg/kg, with a slight effect at 100 mg/kg. The data indicate that pentoxifylline is effective at increasing relative tumour perfusion, with minimal effects on other tissues, and this increase is reflected in improved radiosensitivity. The doses at which the drug is effective are compatible with the mechanism being modification of blood cell deformability. Pentoxifylline shows promise as a clinical radiosensitiser acting by direct increase in tumour oxygenation.

The effect of combining the oxyhemoglobin-modifying drug BW12C with mitomycin C was investigated in a Phase I study of 18 patients with advanced gastrointestinal cancer. The dose of BW12C was increased from 20 mg/kg to 50 mg/kg to modify the hemoglobin-oxygen saturation curve by up to 48%. The period of maximum modification was then prolonged for up to 3 hr by a maintenance infusion of 4-6 mg/kg/hr. Pharmacokinetics of BW12C and mitomycin C were performed in all patients. Peak levels of BW12C increased from 139 micrograms/ml to 378 micrograms/ml. Plasma half life was independent of dose, with an average of 3.3 hr. BW12C was well tolerated with no severe side effects. Three patients had objective tumour responses.

Tumor blood flow modification is currently under investigation as a possible means of optimizing current cancer therapies, with particular respect to improving the efficacy of bioreductive agents. A variety of calcium channel blockers have been shown to modify tumor perfusion in model systems, and may be valuable as potentiators of both bioreductive and conventional drugs. We report the effects of nifedipine, verapamil, flunarizine, and cinnarizine on renal function in C3H mice, assayed by clearance of simultaneously injected 51 Cr ethylenedlamine tetraacetate. Nifedipine at 10 mgkg −1 blocked 51 Cr ethylenediamine tetraacetate clearance for 30 min and reduced its subsequent rate of clearance by a factor (± 2 se) of 2.4 ± 0.6. At 1 mgkg −1 it reduced the rate of clearance by a factor of 1.2 ± 0.2. Verapamil at 10 mgkg −1 blocked 51 Cr ethylenediamine tetraacetate clearance by a factor of 1.2 ± 0.2. Verapamil at 10 mgkg −1 blocked 51 Cr ethylenediamine had no effect at 1 mgkg −1 Flunarizine had no effect at 50 mgkg −1 or at 5 mgkg −1 but cinnarizine at 50 mgkg −1 reduced clearance rate by a factor of 1.2 ± 0.1. The data show that some of these vasoactive agents, nifedipine and verapamil in particular, can severely compromise renal function and may, therefore, affect the plasma pharmacokinetics of co-administered drugs that are cleared by the kidney.

A novel non-immunosuppressive cyclosporin [corrected], PSC-833, has been tested for its ability to circumvent resistance to doxorubicin, vincristine and colchicine in human and murine multidrug resistant (MDR) cell lines. This compound is shown to be a highly potent resistance modifier, being 7-10-fold more potent than the parent compound, cyclosporin A, whilst approximately equal to cyclosporin A in the growth inhibitory effects of compound alone. Reversal of the P-glycoprotein-associated MDR drug accumulation defect is a major component of resistance reversal for PSC-833, as it is for cyclosporin A.

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) are under evaluation as single agents (Phase III) and in combination (Phase I). Ro 03-8799 produces an acute, transient central nervous system syndrome, whereas SR 2508 causes cumulative, peripheral neurotoxicity; both effects are dose-limiting. Pharmacokinetic studies have shown the importance of area under the plasma drug concentration versus time curve (AUC) in predicting the risk of peripheral neuropathy. Most patients have very similar pharmacokinetic parameters. This study reports 2/25 patients receiving 0.75 g/m2 Ro 03-8799 plus 2.0 g/m2 SR 2508 who showed significant discrepancies in drug handling. One patient exhibited a markedly elevated AUC and prolonged t1/2 beta for SR 2508 and this was associated with an unusually rapid onset of peripheral neuropathy. A second patient showed normal handling of SR 2508 but prolonged values for both t1/2 alpha and t1/2 beta for Ro 03-8799 and unusually low levels of its N-oxide metabolite. In addition a low peak Ro 03-8799 concentration combined with a very high volume of distribution was found in this patient, leading to a normal AUC value and toxicity profile. Both patients exhibited a relatively low creatinine clearance. The mechanisms which may underlie these findings are discussed, and the importance of pharmacokinetic monitoring in the use of these agents is emphasized.

The hypoxic cell radiosensitizers Ro 03-8799 and SR 2508 have different clinical toxicities. The former produces an acute but transient central nervous system syndrome, whereas the latter produces cumulative peripheral neuropathy. Following single dose studies, an escalating multiple dose schedule using both drugs in combination showed no unexpected adverse reactions at lower doses. This study identifies the clinical tolerance and pharmacokinetics when doses in the region of the maximal tolerated dose are given to 26 patients receiving infusions of 0.75 g/m2 Ro 03-8799 and 2 g/m2 SR 2508 three times per week. At 15 doses, 3/4 patients experienced WHO grade 2 peripheral neuropathy, whereas at 12 doses 1/9 developed grade 2 and 6/9 developed grade 1 neuropathies. This represents a lower dose of SR 2508 than can be given alone suggesting that some interaction between the two drugs does exist in terms of chronic peripheral neurotoxicity. Pharmacokinetic studies show no adverse interactions between the two drugs and minimal inter-patient variation. From bivariate analysis, cumulative AUC for Ro 03-8799 has the most significant correlation with the development of peripheral neuropathy. Tumor drug concentrations normalized to the administered dose show mean values of 34 micrograms/g Ro 03-8799 and 76 micrograms/g SR 2508 30 minutes after infusion. These could be expected to produce a single dose sensitizer enhancement ratio of 1.5. The combination of the two sensitizers at the maximum tolerable dose may be expected to give an increased therapeutic efficacy over either drug alone.

Since the work of Moon and Richards (I), the 3’P chemical shift of inorganic phosphate (Pi) has been widely used as an indicator of the pH of biological systems. In blood, the Pi resonance often overlaps the doublet resonance of 2,3-diphosphoglycerate (2,3-DPG) and several spectral editing techniques to separate them have been suggested (2-4). However, all of those techniques require a delay of 1/2J,n(n in this method the delay between excitation and acquisition can be much less than 1/2n the 180” pulse refocuses any dephasing due to magnetic field inhomogeneity and the evolution due to chemical shift. Any evolution due to heteronuclear scalar coupling is also refocused. Consequently, both the components of the DPG doublet and Pi will have the same phase. In the second sequence, a 180” pulse is applied at the 31P and ‘H frequencies. Since the 180” proton pulse inverts the spin states of the proton spins, the evolution due to the heteronuclear scalar coupling of the DPG doublet is not refocused. Therefore at the end of the sequence, one of the resonances of the doublet would have evolved through an angle of hJpH, and the other through -rJpH (= kq5). However, the magnetization of the Pi singlet will have the same phase as before. The positions of the magnetization vectors after the two sequences are illustrated in Fig. 2 as EXP 1 a and EXP lb. The phase of the FID acquired with the sequence in Fig. 1 b is now rotated through k,$. When this FID is subtracted from that resulting from the sequence in Fig. lA, one peak of the DPG doublet cancels out, leaving the singlet from the Pi, plus the

The 2-nitroimidazole hypoxic cell radiosensitizer Ro-03-8799 has been suggested to have possible advantages over misonidazole with regard both to radiosensitization and toxicity on the basis of reported experimental work. The present work reports a Phase I escalating dose toxicity study of the drug. This has shown severe acute central neurotoxicity at high dose levels (greater than 1 g/m2). Initial results of a multiple-dose toxicity study indicate that 1 g/m2 is likely to be the maximum dose which may be given repeatedly. The plasma and tumor pharmacokinetics of the drug have been measured. The mean t 1/2 for 9 patients was 5.8 +/- 1.5 hr. Peak plasma concentration is linearly related to dose and at 1 g/m2 is 12.1 +/- 2.3 micrograms/ml (n = 6). Human tumor drug concentrations have been measured after single doses of 1 g/m2 given to 8 patients with a variety of tumors. Peak tumor concentrations of drug of 11.7-81.6 micrograms/g were found. Because of acute, dose-limiting toxicity related to individual doses it may not be possible to achieve, in human tumors, concentrations of drug that offer significant advantage over misonidazole in terms of radiosensitizing efficiency. No evidence of chronic cumulative toxicity was observed at the doses employed.

In a randomized, double-blind study, 44 patients with recurrent high grade malignant glioma were allocated to chemotherapy of CCNU, with or without benznidazole (BENZO). Of 42 eligible patients, 23 received CCNU alone, and 19 CCNU received BENZO. Only 8 patients received the full 6 courses of treatment. The mean number of courses given was 2.8 for placebo and 3.4 for benznidazole patients. Progressive disease caused termination of treatment early for the majority of patients. There was no evidence of increased toxicity-leucopenia, anemia or thrombocytopenia-in the BENZO group, and only one patient in each treatment group had chemotherapy terminated because of toxicity. The BENZO group did not demonstrate any survival advantage: median survival time was 25 weeks in the BENZO group and 30 weeks in the placebo group. The confidence interval for the treatment difference is wide but excludes a BENZO-related addition of more than 7 months to the median survival time.

The problems of the combined modality treatment of inoperable lung cancer are discussed in this paper. There is a lack of secure data on optimal radiation dose and fractionation schedules when this is the sole treatment. The problem is compounded in the combined modality situation by the possibility of increased toxicity. Whereas there is effective chemotherapy for small cell carcinoma and evidence for improved results in combined modality treatments, the results of such treatments for non-small cell carcinoma are disappointing. Strategies for improving the results are discussed.

The hypoxic cell radiosensitising drug misonidazole, [ 1 -( 2 -nitroimidazol- 1 -yl)- 3 -methoxypropan- 2 -ol, Ro 07-0582 ] was administered to dogs at dose levels of 50–200 mg/kg on four consecutive weekly occasions by oral and intravenous routes. High-performance liquid chromatography was used to monitor the subsequent plasma concentrations of misonidazole and its 0 -demethylated metabolite [ 1 -( 2 -nitroimidazol- 1 -yl)- 2,3 -propandiol, Ro 05-9963 ]. Both misonidazole and Ro 05-9963 were also detected in the urine in the free and glucuronide-conjugated forms. The detailed pharmacokinetics of misonidazole in the dog are presented and some observations are made on the toxicity of the drug in this species. We conclude in the light of these pharmacokinetic data that the dog may prove to be a better model for the study of misonidazole than those presently used in the laboratory, particularly the rodent species.

It is technically difficult to heat tumors in the thorax. Whole body heating gives the best tumor temperature distribution but is limited to 42°C, while external RF heating is uncertain. Implant techniques may be worth developing to overcome some of these problems. Hyperthermia alone is ineffective and needs to be combined with radiotherapy or chemotherapy. Does hyperthermia have a place in the management of lung cancer? As clinical results remain largely anecdotal, it can only be recommended as an experimental technique to be studied within the framework of well-designed clinical trials.

Growth studies show that neurotensin and its amino- and carboxy-terminal sequences inhibit the growth of small cell lung cancer cell lines in vitro. Growth inhibition by neurotensin is concentration-dependent and apparently not mediated by specific, high affinity neurotensin receptors.

The expression of monoclonal antibody (Moab)-defined lung tumour antigens has been investigated in in vitro -derived multidrug-resistant (MDR) variants of small cell (SCLC) and non-small cell (NSCLC) lung tumour cell lines. The majority of Moabs tested reacted equally well with MDR and drug-sensitive SCLC and NSCLC cells. However, in contrast to drug sensitive SCLC cells, MDR-SCLC cells failed to express the glycolipid antigen defined by Moab LCA1/LC38, showed increased expression of 2 glycoproteins, defined by Moabs LAM8 and SWA 4, and increased expression of the sugar epitope defined by Moab MOv15. Drug resistant large cell lung cancer cells also showed increased expression of the glycoprotein defined by Moab SWA 4 compared to the parent line which failed to react with this Moab. No significant differences were observed in the expression of lung tumour antigens by drug sensitive and resistant adenocarcinoma cells.

The relationships between classic and variant small cell lung cancer (SCLC) cell lines and between variant SCLC (SCLC-V) and non SCLC (NSCLC) cell lines has been explored using a panel of selected monoclonal antibodies (Moabs). The aims of this study were to identity cell surface antigenic phenotypes which characterise the various lung tumour types and to relate the expression of lung tumour antigens to differentiation status. These studies have identified antigenic phenotypes that (1) distinguish classic from variant SCLC cell lines; (2) distinguish SCLC (irrespective of subtype) from NSCLC; (3) correlate with the expression of L-dopa decarboxylase, neuron specific enolase and creatine kinase BB.