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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.

Combining hyperthermia, an experimental/adjuvant therapeutic modality for cancer, with the non-invasive metabolic studies using Magnetic Resonance (MR) is an interesting area of research. This two parts article discusses the development and testing of a conventional RF hyperthermia applicator for MR studies and vice versa. In this first part, an inductive type applicator known as 'Magnetrode' in RF hyperthermia has been used both as an MR volume resonator and a surface coil. Its concurrent performance as an hyperthermic applicator and an MR transmit/receive coil has been evaluated.

DACA, also known as XR5000, is an acridine derivative active against both topoisomerase I and II. In this phase I study, DACA was given as a 3-h intravenous infusion on 3 successive days, repeated every 3 weeks. A total of 41 patients were treated at 11 dose levels between 9 mg m(-2) d(-1) and the maximum tolerated dose of 800 mg m(-2) day(-1). The commonest, and dose-limiting, toxicity was pain in the infusion arm. One patient given DACA through a central venous catheter experienced chest pain with transient electrocardiogram changes, but no evidence of myocardial infarction. At the highest dose levels, several patients also experienced flushing, pain and paraesthesia around the mouth, eyes and nose and a feeling of agitation. Other side-effects, such as nausea and vomiting, myelosuppression, stomatitis and alopecia, were uncommon. There was one minor response but no objective responses. DACA pharmacokinetics were linear and did not differ between days 1 and 3. The pattern of toxicity seen with DACA is unusual and appears related to the mode of delivery. It is possible that higher doses of DACA could be administered using a different schedule of administration.

Transient plugging of microcapillaries by leucocytes is a possible reason for the occurrence of acute hypoxia in tumours. We compared the abilities of nicotinamide at 1000 micrograms ml-1 and 150 micrograms ml-1 and pentoxifylline at 300 micrograms ml-1 to increase the filterability of normal and artificially activated human leucocytes through 8 microns pores, as a model for the capillary bed. Using a St George's filtrometer, filterability of treated leucocyte suspensions was compared with control for three to six sequential 60 microliters samples, normalising control values to unity. Pentoxifylline at 300 micrograms ml-1 halved the ratio of treated to control value to 0.47 +/- 0.13 (2 s.e.), P = 0.001 (i.e. an increase in filterability), and nicotinamide at 1000 micrograms ml-1 reduced it to 0.69 +/- 0.22, P = 0.04, but the clinically achievable 150 micrograms ml-1 was ineffective (0.82 +/- 0.25, P = 0.24). Filterability of artificially activated leucocytes was reduced (3.9 +/- 1.20) but was restored to control values of unity by 1000 micrograms ml-1 nicotinamide and 300 micrograms ml-1 pentoxifylline and partially restored by 150 micrograms ml-1 nicotinamide (1.2 mM), which was isoeffective with 100 micrograms ml-1 pentoxifylline (0.37 mM). Pentoxifylline is therefore more effective on a molar basis and was shown to affect both polymorphonuclear leucocytes and lymphocytes, while nicotinamide only affects lymphocytes. The data are consistent with the hypothesis that both agents modify acute hypoxia by increasing leucocyte filterability.

Purpose: To determine the maximum-tolerated dose (MTD) and toxicity of PSC 833 infusion administered with etoposide for 5 days in patients with cancer, and to determine the effect of PSC 833 on etoposide pharmacokinetics., Patients and Methods: Thirty-five patients were entered onto the study, one of whom was ineligible. Etoposide was delivered from day 1 as a 2-hour infusion over 5 consecutive days at a dose of 75 to 100 mg/m2/d. PSC 833 was administered from day 2 as a 2-hour loading dose and as a 5-day continuous infusion. Doses were escalated from 1 to 2 mg/kg (loading dose) and 1 to 15 mg/kg/d (continuous infusion)., Results: Thirty-four patients were treated with 53 cycles of PSC 833 and etoposide. Steady-state blood PSC 833 levels more than 1,000 ng/mL were achieved in all patients treated at PSC 833 doses > or = 6.6 mg/kg/d by continuous infusion. Myelosuppression was the most common toxicity. The major dose-related toxicity of PSC 833 was reversible hyperbilirubinemia, which occurred in 83% of cycles. The dose-limiting toxicity of PSC 833 was severe ataxia, which occurred in two of nine patients treated at 12 mg/kg/d and in both of the single patients treated at 13.5 and 15 mg/kg/d. PSC 833 concentrations more than 2,000 ng/mL resulted in an increase in etoposide area under the curve (AUC) of 89%, a decrease in etoposide clearance (Cl) of 45%, a decrease in volume of steady-state distribution (Vss) of 41%, and an insignificant increase in alpha half-life (t 1/2 alpha) and significant increase of beta half-life (t 1/2 beta) of 19% and 77%, respectively., Conclusion: PSC 833 can be administered in combination with etoposide with acceptable toxicity. The recommended continuous infusion dose of PSC 833 for this schedule is 10 mg/kg/d over 5 days. PSC 833 results in an increase in etoposide exposure and etoposide doses should be reduced in patients receiving PSC 833.

Nicotinamide and carbogen breathing are both effective radiosensitisers in experimental tumour models and are even more effective in combination. This study was to investigate the feasibility of using the agents in combination in patients and to measure their effect on tumour oxygenation. Twelve patients with advanced malignant disease were treated with 4-6 g of oral nicotinamide (NCT) in tablet formulation. Ten of these 12 patients breathed carbogen (95% oxygen, 5% carbon dioxide) for up to 20 min at presumed peak plasma NCT concentration (Cpeak) and had tumour oxygen partial pressure (pO2) measured using the Eppendorf pO2) histograph. The mean Cpeak values were 82, 115 and 150 micrograms ml-1 for NCT doses of 4, 5 and 6 g respectively and were dose dependent. The time of Cpeak was independent of dose with an overall mean of 2.4 h (range 0.7-4 h). NCT toxicity occurred in 9 out of 12 patients and was mild in all but one; carbogen was well tolerated in all patients. Following NCT only two patients had significant rises (P < 0.05) in tumour median pO2. During carbogen breathing, eight out of ten patients had early highly significant rises in pO2 (P < 0.0001), of which six continued to rise or remained in plateau until completion of gas breathing. Six patients had hypoxic pretreatment values less than 5 mmHg, which were completely abolished in three and reduced in two during carbogen breathing. In conclusion, the combination of NCT and carbogen breathing was generally well tolerated and gave rise to substantial rises in tumour pO2 which were maintained throughout gas breathing. These results should encourage further study of this potentially useful combination of agents as radiosensitisers in the clinic.

Tumour tissue oxygenation has been measured in man during carbogen breathing (95% O2, 5% CO2) using a commercially available polarographic electrode system (Eppendorf p02 histograph). At least 200 tumour measurements in each of 17 patients with accessible tumours were taken before, and subsequently continuously after the commencement of carbogen breathing for periods of 10 to 30 min. In 12 out of 17 patients studied there was a significant increase in median tumour p02 during the first 10 min of carbogen breathing (range 9 to 1800%). There was an initial rapid increase in tumour p02 which was maintained until 8 to 12 min, but then decreased throughout the subsequent treatment period. Although there was a reduction in the proportion of point measurements < or = 10 mmHg in 11 out of 13 patients, during carbogen breathing, measured points of < or = 2.5 mmHg were only eliminated in three out of 11 tumours. The time course has implications for the planning of clinical trials utilising radiotherapy with carbogen breathing.

The secretion of insulin-like growth-factor-binding proteins (IGFBPs) and expression of the genes encoding IGFBP-1, IGFBP-2 and IGFBP-3 have been studied in a panel of cell lines derived from breast carcinomas, Wilms' tumour, neuroblastoma, retinoblastoma, colon carcinoma, liver adenocarcinoma, Burkitt's lymphoma and a non-small-cell lung carcinoma. All cell lines, with the exception of the Burkitt's lymphoma cell line, secreted IGFBPs, as detected by affinity labelling. A 34-kDa BP was present in the conditioned media of all IGFBP-secreting cell lines, whereas BPs ranging from 18 kDa to 53 kDa were variably secreted. All IGFBP-secreting cell lines expressed the IGFBP-2 gene as determined by Northern blot analysis. The Wilms' tumour, the neuroblastoma and the retinoblastoma cell line expressed the IGFBP-2 gene only. All other cell lines, with the exception of the Burkitt's lymphoma, expressed the IGFBP-2 gene and, in addition, either the IGFBP-1 gene and/or the IGFBP-3 gene. IGFBP-1 gene expression could be detected by reverse transcriptase polymerase chain reaction only. IGFBP-3 gene expression was detected by Northern blot analysis, but transcripts were less abundant than IGFBP-2 mRNAs. These findings indicate that the expression of multiple BP genes and the secretion of BPs may be a common property of tumour cells.

The two radiosensitizers etanidazole and pimonidazole, currently in clinical phase 3 trials, have different toxicities. The former produces a peripheral neuropathy after cumulative doses and the latter presents an accurate but transient central nervous system syndrome after each dose. A strategy for improving on the maximum radiosensitization achievable using either drug alone, has been investigated in the study reported in this paper. Escalating doses of the two drugs were given together to determine toxicity up to a maximum of 15 doses of 2.0 g/m2 etanidazole and 0.75 g/m2 pimonidazole/dose. 25 neuropathies were seen in the total of 48 patients (48%). This included 6 grade 2 neuropathies (12.5%) or 15% of those receiving 9 or more infusions. There were no significant correlations between the incidence of neuropathy and various dose and AUC parameters for the 31 patients receiving 10 or more infusions. However, in the selected group of 26 patients planned to receive multiple doses of etanidazole at 2 g/m2/dose with pimonidazole at 0.75 g/m2, significant correlations were seen with the cumulative dose, with single and cumulative AUCs for pimonidazole and also for the cumulative dose and the cumulative AUC for etanidazole, but not its single AUC. In the light of these observations and the recent reports of higher peripheral neuropathy rates than previously reported in studies in the USA, it is concluded that it is not possible at this time to determine whether there is toxicity interaction between the two drugs. There remains the possibility that, on the basis of the combined drug dosage achieved, an increased therapeutic efficacy can be reached with either drug alone.

The clinical use of hyperthermia for the treatment of cancer continues to be hampered by technical difficulties. Current methods of local heating do not give satisfactory heat profiles. The biological concepts behind the potentially successful use of this treatment modality are discussed together with a review of the advantages and disadvantages of the various techniques employed. Some clinical studies using microwaves and radiofrequency heating are reviewed.

The hypoxic cell-radiosensitizing drug misonidazole (1-(2-nitroimidazol-1-yl)-3-methoxypropan -2 -ol, Ro 07-0582, MIS) was administered at a dose of 150 mg/kg i.v. to 6 dogs bearing spontaneous tumours, and the resulting tumour concentrations were measured to HPLC analysis. In 4 dogs it was possible to obtain serial biopsy specimens up to 5 h. With the exception of a brain tumour, the tumour concentrations ranged between 47% and 95% of the plasma concentration, most of the values falling within the range 50--70%. Concentrations in the brain tumour were markedly lower. Barbiturate anaesthesia was necessary for the removal of the serial biopsy specimens, and the effects of sodium pentobarbitone anaesthesia on the pharmacokinetics of MIS were investigated in 2 dogs. After barbiturate anaesthesia peak plasma concontrations were raised and the availability of MIS was increased, although the biological half-life remained unaltered. The metabolism of MIS to the O-demethylated metabolite, Ro 05-9963, was delayed initially. The concentrations of MIS AND Ro 05-9963 in cerebrospinal fluid were also recorded in these dogs; MIS concentrations were found to approach those of the plasma, whereas the metabolite concentrations were considerably lower (0--58% of the plasma concentration).

Ro 03-8799 is a lipophilic, basic 2-nitroimidazole of greater potency than misonidazole, which we have administered to 52 patients. The dose-limiting toxicity is an acute central nervous system toxicity with symptoms which include nausea, disorientation, sweating, a feeling of heat and, in one extreme case, coma. Pharmacokinetic analysis was carried out in 31 patients. The mean distribution phase half-life was 44 min and the mean elimination half-life was 6.1 h. Peak concentration was linearly related to dose over the range 0.25 g/m2 to 3 g/m2 with a mean at 1 g/m2 of 15.7 micrograms/ml. Area under the curve was also linearly related to dose and the average whole body clearance was 20.1 l/h. Urinary recovery at 24 h was 31% for the parent compound and 28% for the N-oxide metabolite. The drug is concentrated in normal brain, brain tumour and non-brain tumour to a similar extent, the respective mean tissue/plasma ratios being 381%, 329% and 355%. For a dose of 1 g/m2, tumour concentrations were 1.5 times as high as for misonidazole, and the available in vivo and in vitro sensitisation data predict as improvement of 1.8 and 3.3 times respectively.

The 2-nitroimidazole benznidazole (BENZO) has previously been shown to be an effective potentiator of the cytotoxicity of CCNU in mice, at levels which are achievable in man. This enhancement is greater than that for normal tissues, resulting in a therapeutic gain. In this study BENZO has been given to 46 patients in oral doses of 4 mg/kg to 30 mg/kg, and drug concentrations measured in plasma, urine, tumor and normal brain by HPLC. The mean plasma t 1/2 was 12.8 +/- 0.5 h and plasma peak concentration and AUC0-infinity were linearly related to dose over the whole range. Approximately 60% of the drug was bound to plasma proteins and 6% excreted unchanged in urine. Mean tumor/plasma ratios of 88% (range 54 to 122%) for 11 gliomas and 72% (range 46 to 103%) for 6 superficially accessible non-brain tumors were obtained while that for normal brain was 69% (range 53 to 75%). Doses of more than 17 mg/kg BENZO produce changes in the plasma pharmacokinetics of CCNU (130 mg/m2 p.o.), increasing the half life of active hydroxylated metabolites. In addition, CCNU parent compound is present. This is not seen when CCNU is given alone. Such changes may result in improved response rates as it is possible to achieve in man, plasma and tumor levels of BENZO, which in the mouse model produce effective enhancement of the response to CCNU. No evidence was seen that BENZO enhanced wither the acute gastrointestinal toxicity or the hematological toxicity of CCNU over the dose range studied.

A total of 41 superficial tumours have been treated with radiation alone (21 lesions) or in combination with hyperthermia (20 lesions) in a non-randomized study on 16 patients. A minimum tumour heat dose in excess of 30 min equivalent at 43 degrees C was achieved in 46 of the 80 (57 per cent) hyperthermia treatments. Small lesions received better quality heat treatments and were more likely to achieve a complete response. There is a significant increase in the response of lesions treated with the combined modality compared with radiation alone (P less than 0.01). Similar results were obtained when matched lesions with internal controls were analysed separately. There was an increased incidence of severe skin reactions in the hyperthermia-treated group with the reaction tending to develop more quickly. There were three instances of late fibrosis in the hyperthermia group. There is a significant correlation between the severity of the skin reaction and the average maximum skin heat dose per treatment.

The hypoxic cell radiosensitizers Ro 03-8799 (pimonidazole) and SR 2508 (etanidazole) have differing physico-chemical properties and clinical toxicities. The former is basic, lipophilic and produces an acute but transient central nervous system syndrome; the latter is neutral, hydrophilic and causes cumulative peripheral neuropathy. We therefore investigated the possibility of combining these agents to achieve additive radiosensitization with no enhancement of toxicity, as demonstrated in a rodent tumor model. Following a single dose study which showed a lack of interaction with respect to both toxicity and pharmacokinetics, twenty-one patients have now completed simultaneous drug administration on an escalating, multiple dose schedule. There has been no adverse acute interaction up to 0.75 g/m2 Ro 03-8799 with 2 g/m2 SR 2508 for 15 doses. At this dose-level, however, all patients experienced peripheral neuropathy. There was no adverse pharmacokinetic interaction, or perturbation of plasma pharmacokinetics between initial and final infusions. Tumor concentrations were determined in 48 biopsy samples 0-60 min after administration. Mean values normalized to a dose of 0.75 g/m2 Ro 03-8799 plus 2 g/m2 SR 2508 were 33 micrograms/g Ro 03-8799 and 74 micrograms/g SR 2508. These would be expected to produce a single-dose sensitizer enhancement ratio of around 1.5. The combination is predicted to be around 6.8 times more active than misonidazole, and superior to any single agent tested to date. The current schedules are reaching the limits of clinical tolerance, and an attempt is now being made to define the optimal regimen for use in a randomized clinical trial of the combination.

A range of new anthracyclines, structurally related to adriamycin (ADM), has been synthesised and studied in vitro. Three compounds described in this paper (Ro 31-1215; Ro 31-1741; Ro 31-2035) are all 4-demethoxyanthracyclines. In the mouse mammary tumour cell line, EMT6/Ca/VJAC, using a 1 h drug exposure followed by colony formation as the response endpoint, we found Ro 31-1215 and Ro 31-1741 to be 2-3 x and 4-7 x more potent then ADM, whilst Ro 31-2035 was 3-4 x less potent. For continuous drug exposure and suppression of population growth as the endpoint, the potency of Ro 31-1741 was similar to that of ADM, whereas that of Ro 31-1215 was 1.5-2 x higher and that of Ro 31-2035 was 10-20 x lower. The potency ratios for continuous drug exposure of a human small cell lung cancer line were similar to those for continuous exposure of EMT6. Variants of the two cell lines selected for resistance to ADM were also studied. These variants also showed considerable resistance to Ro 31-1741 and Ro 31-2035 but much less resistance to Ro 31-1215 (a 9-methyl derivative). A variant of EMT6 made resistant to Ro 31-1215 by continuous growth in this drug was more resistant to ADM than it was to Ro 31-1215. Human cells resistant to ADM contained 6 x less ADM after 24 h exposure than did the parent line, whereas the ratio of drug content for Ro 31-1215 was only 2.

A clinical hyperthermia system using a 915 MHz microwave generator and incorporating multipoint thermocouple thermometry is described. Temperatures can be monitored simultaneously at 16 points and measurements displayed on a visual display unit and a plotter. The power output of the generator is adjusted under computer control to maintain a constant predetermined temperature in a chosen control channel. A clinically useful feature of the system is the ability to determine the effective cumulative thermal dose delivered to the tissue at points monitored in real time. The basis for the thermal dose calculation is discussed in detail. The calculated dose parameter is displayed for each of the 16 channels during the treatment and updated every 30 s. This real-time display of a thermal dose parameter has made possible a more homogeneous heating of tumours.

A prospective study was conducted to study the effect of radiotherapy (RT) and regional pelvic hyperthermia (HT) on intestinal permeability in three groups of patients. Fifteen acted as cancer controls, receiving RT away from the peritoneal cavity, 21 patients received radical pelvic or abdominopelvic RT and 13 patients pelvic RT followed by pelvic HT using a BSD 1000 phased array applicator. Small bowel permeability was measured by oral administration of a mixture of [51Cr]EDTA, [14C]mannitol and lactulose before and after a course of treatment. The absorption of each marker was calculated by measuring the urinary excretion over 0-6 and 0-12 hours. The 6 hour collection gave results similar to the 12 hour collection, but had logistical advantages. The EDTA absorption rose and the mannitol absorption fell during a course of treatment, but the best index of permeability change was the EDTA/mannitol ratio (E/M). The E/M ratio rose by a factor of 2.4 (P less than 0.001) and 1.82 (P = 0.05) following RT and RT/HT respectively. There was no significant difference between the RT and RT/HT groups but the thermal dose to the RT/HT group was low (23 min./equiv 43 degrees C over three or four fractions in 4 weeks). There was no correlation between small bowel permeability and bowel frequency. The E/M permeability test is a useful simple functional assay for assessing small bowel damage after RT and RT/HT.

The combined use of drugs and radiation in the treatment of cancer in man is reviewed. In most studies the combined result cannot be demonstrated to show more than an additive effect of the individual treatments. This may result in no more than an increase in toxicity and lack of gain. In others, therapeutic synergism is demonstrated by a spatial co-operation between the modalities. The critical questions concerning combined modality treatments are indicated and discussed, with particular reference to bleomycin. It is concluded that more careful randomised clinical trials with appropriately defined endpoints are required.