Hyperthermia and chemotherapy: when will they be used in the clinical treatment of cancer?
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Biomedical subjects
Publications and source records attributed to R L Magin.
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A minicomputer-based system was designed to control the microwave (2.45-GHz) power to four local hyperthermia applicators. Errors in temperature measurement, due to electromagnetic field interactions with small thermocouple probes, are minimized by sampling the temperature only when the microwave power is off. The programmable controller can regulate the temperature in tumors in 0.1 degree C increments from 30 to 60 degrees C. This technique reduces temperature differences throughout the tumor at steady state to less than 0.4 degrees C and prevents skin burns.
A system for applying local hyperthermia employing ultrasonic transducers with annular focusing lenses gave better temperature uniformity in small fibrosarcomas than conventional unfocused transducers. The lenses were designed for ultrasonic frequencies of 3, 4, 5 and 9 MHz for tumors approximately 6 mm dia. Tests in degassed water indicated that the focusing lenses concentrated approx. 80% of the ultrasonic energy into an annular-shaped focus of 6 mm dia. located at a distance of 3 cm in front of the lens. These transducers were used to heat subcutaneous PARA-7 fibrosarcomas in hamsters. Steady-state temperature measurements indicated temperature gradients within tumors of 0.5-1.0 degree C when transducers employing annular-focused lenses were used, versus gradients of 2.0-2.3 degree C with 10 mm dia. unfocused transducers.
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Liposomes with phase transitions a few degrees above physiological temperature delivered more than four times as much methotrexate to murine tumors heated to 42 degrees C as to unheated control tumors. Most of the accumulated drug appeared to be intracellular and bound to dihydrofolate reductase, the enzyme blocked by methotrexate in its role as an antineoplastic agent.
The sensitivity to local tumor hyperthermia (43 degrees, 60 min) of a spectrum of eight different solid mouse tumors (Lewis lung carcinoma, M5076 ovarian carcinoma, colon carcinoma 38, colon carcinoma 26, mammary adenocarcinoma C3HBA, mammary adenocarcinoma 16C, glioma 26, and B16 melanoma) was investigated. A microwave (2.45-GHz) apparatus produced localized heating of the tumors without generation of whole-body hyperthermia. The temperature at the center of the heated tumors was regulated to within +/- 0.1 degrees while the temperature uniformity within the tumor was +/- 0.5 degrees. The local hyperthermia treatments reduced the size and retarded the growth of the treated tumors compared with control values for each of the tumors tested. The faster-growing Lewis lung carcinoma and B16 melanoma were the least responsive to treatment, while the slower-growing colon 38 and M5076 ovarian carcinomas were the most responsive. Multiple treatments resulted in longer grwoth delays and greater tumor growth inhibition than did single treatments. No consistent difference in life span between the control and treated groups was measured, and only five of 188 treated animals were cured.
The cytotoxicity of the drug bleomycin in vitro has previously been shown to be enhanced by hyperthermia. This report demonstrates in vivo a more than additive interaction between local tumor hyperthermia (43 degrees, 60 min) and bleomycin (15 mg/kg s.c.) against s.c.-implanted Lewis lung carcinomas in mice. Local hyperthermia was produced by the application of 2450-MHz microwaves to the region of the tumor without induction of significant whole-body hyperthermia. The combined drug and heat treatments were applied to tumors on Days 4, 7, and 10 following implantation. The response of the tumors to simultaneous treatment was a 17-day growth delay compared with controls, whereas the local hyperthermia and bleomycin individually resulted in only 3- and 4-day growth delays, respectively. If the two treatments were given either 4 or 24 hr apart only an additive effect on growth delay was observed.
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The RIGR (reduced-encoding imaging by generalized-series reconstruction) technique for magnetic resonance imaging uses a high-resolution reference image as the basis set for the reconstruction of subsequent images acquired with a reduced number of phase-encoding steps. The technique allows increased temporal resolution in applications requiring repeated acquisitions, such as the dynamic imaging of contrast agent biodistribution, and in intrinsically time-consuming protocols such as the acquisition of a series of T2-weighted images. Several examples are presented to demonstrate that a four- to eightfold improvement in spatial or temporal resolution can be achieved with this technique.
An understanding of the cellular permeability for water is needed to evaluate MR images of complex tissues, such as liver, and to interpret the effects of contrast agents. To obtain data essential for such an understanding we measured water exchange across the isolated rodent hepatocyte membrane by proton NMR relaxation with dextranmagnetite as a relaxation agent. The results are treated as water exchange in a two-compartment system, and possible reasons for deviations from that behavior are analyzed. The mean residence time of intracellular water was approximately 40 ms at 37 degrees C. We found the lower limit for the diffusional permeability of the hepatocyte membrane to be 8 x 10(-3) cm s-1. These results, combined with consideration of hepatic anatomy indicate that the failure to observe effects on the T1 of liver from particulate contrast agents such as magnetite, Gd-starch, and liposome encapsulated Mn2+ is due to the localization of these agents in the Kupffer cells. Also, the nonexponential T1 decay observed in normal liver is unlikely to be due to slow exchange of water between compartments.
The biological and physical properties of albumin and nitroxides make them attractive candidates as special purpose MRI contrast agents which could be used to study the intravascular compartment or specific targets in tissues. In this study, albumin-nitroxide complexes were prepared by reduction and alkylation of the disulfide bonds of the protein and characterized by electron spin resonance and ultraviolet absorption spectroscopy. An average of six nitroxides were bound covalently to each molecule of human serum albumin. The water proton relaxivity of the protein-bound nitroxide (at 20 MHz and 37 degrees C) was 4-fold greater than that of the free nitroxide. The digestion of the nitroxide-albumin complexes by cells or by trypsin decreased the relaxivity of the nitroxide-protein complex. The rate of reduction of albumin-bound nitroxide by cells was much slower than that of the free nitroxide but still was oxygen-sensitive (2-3-fold increase in the rate of reduction in the absence of oxygen).
Acoustic field patterns from a planar multi-element ultrasonic applicator were determined experimentally and compared with theory. Measurements were obtained from square arrays of 4 and 16 elements. The acoustic fields produced by various configurations of individual square elements (3.6 cm X 3.6 cm) driven at 1 MHz were measured in water. Transverse and axial scans paths were used to characterize the acoustic beam for different aperture sizes and individual element excitations. Unequal power excitation of adjacent elements produced multiple peaked acoustic intensity patterns. While a simple theoretical model was not able to account for all the experimentally determined transverse and axial field patterns, a model including mechanical damping improved the agreement between theory and experiment. However, less ripple in the axial pattern was measured than predicted by either theoretical model. The ability of the applicator to generate acoustic field patterns suitable for local tissue heating was demonstrated by an experimental study in dog thigh muscle.
Microwave energy has proven useful for treating superficial tumours in the head, neck and chest regions. Currently, multi-element phased arrays are being proposed to upgrade clinical capabilities for localized microwave hyperthermia. When compared with a single radiating element, phased array applicators are expected to provide deeper tissue penetration, reduce undesired heating of normal tissues between the applicator and tumour, and improve local control of the tumour temperature distribution. This paper surveys recent developments in the design and characterization of phased arrays, identifies anatomical and physiological factors that complicate successful clinical treatment and discusses the current state of phased array hardware development for hyperthermia.
The ability to make localized temperature measurements in tissue during hyperthermia treatment of cancer is an essential factor in optimizing its efficacy. To this end we have developed and evaluated the complex tris(ethylenediamine) cobalt(III) trichloride as a temperature sensor by determining the temperature dependence of it 59Co nuclear magnetic resonance chemical shift. Encapsulating this complex within liposomes targets the agent to the reticuloendothelial system. Temperature changes of the order of 0.1 degrees C have been measured in vivo on rats, and the half-life of the complex within the body determined by plasma emission spectroscopy.