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Biomedical subjects

G K Lam

Publications and source records attributed to G K Lam.

At least 37 records · Page 2Linked to original sources
PubMed1992

The response of murine B-16 melanoma to fractionated doses of pions.

The relative biological effectiveness (RBE) of pions has been studied in mouse B-16 melanoma transplanted into C57BL/6 mice. To determine the RBE at both high and low doses per fraction, a range of fractionation schedules was used, with 1, 4 and 10 fractions. The reference 250 kV X ray dose rate was 1.5 Gy/min which was much higher than the dose rate of pions (0.25 Gy/min). The RBE varied depending on the number of fractions and, within the same fractionation schedule, also on the dose per fraction. The RBE ranged from 1.15 for single fractions at 12.5 days of growth delay, to 1.80 for 10 fractions at 5 days of growth delay, which was determined by the time taken for the tumors to reach 5 times the average of their original volume. RBEs at the iso-effect level of 10 days growth delay were 1.20, 1.29 and 1.62 for single, 4 fractions and 10 fractions, respectively. RBE values were influenced by both the number of fractions and the dose per fraction, that is, the larger the number of fractions and the smaller the dose per fraction, the larger the value of RBE. In comparison with RBE of normal mouse skin, it was suggested that pion therapy may provide advantage over conventional photontherapy for radioresistant tumors such as this melanoma with the maximum therapeutic gain factor of 1.2. alpha/beta ratios for B-16 melanoma were also obtained from the 10 day growth delay iso-effect curve, and were 10.5 Gy and 32.6 Gy for X ray and pions, respectively.

Animals↗
PubMed1991

A proposed biophysical framework for radiation protection calculations using summation of iso-risk contributions of different radiations.

A biophysical framework for administrative radiation protection calculation using summation of iso-risk contribution of different radiation components is presented. It addresses some of the concerns with the present system but would preserve the present linear mathematical framework and hence the massive literature of numerical calculations in radiation protection.

Biophysical Phenomena↗
PubMed1991

The response of mouse tumours to fractionated doses of pions: determination of therapeutic gain factor.

Using the same experimental system which had been used to determine the pion relative biological effectiveness (RBE) for skin of mouse foot by Chaplin et al., we have determined the pion RBE for KHT sarcoma and SCCVII tumour transplanted in the foot of C3H mice. The pion RBE obtained by the tumour growth delay time method in comparison with 250 kVp X-rays at a dose rate of 150 cGy per min was determined to be 1.20, 1.28 and 1.50 with single, 4 and 10 fractions, respectively, for KHT sarcoma. As for SCCVII tumour, it was determined to be 1.17, 1.45 and 2.05 with single, 4 and 10 fractions respectively. Therefore, it has been concluded that pions have various values of RBE depending on the tumour system involved. KHT sarcoma is a tumour which grows very rapidly, on the contrary, SCCVII tumour shows somewhat slower growth characteristics. These differences of RBE between these two tumour systems possibly stem from differences in the amount of hypoxic cells and/or their rates of reoxygenation. As for therapeutic gain factor, a maximum value of 1.45 was obtained with 10 fractions using the SCCVII tumour. Pions seem to be most effective (in multiple fractions) against tumours of relatively slow growth.

Animals↗
PubMed1990

Preclinical evaluation of pions in vivo: experience at TRIUMF.

This paper describes the results obtained from in vivo studies of the pion beam at the TRI University Meson Facility (TRIUMF). The studies encompass work (from 1978 to 1986), designed to evaluate the RBE for early and late effects and to assess the importance of X-ray dose rate and treatment volume on these values. Results with early responding tissues, i.e. mouse and pig skin and mouse intestine indicate a pion RBE of about 1.5 in the clinically relevant dose per fraction range of 2-3 Gy. At these doses, RBE appears to be independent of the reference X-ray dose rate. However, at high doses per fraction, the RBE values become increasingly X-ray dose rate dependent. The induction of late effects by pions has been assessed by monitoring the late dermal response of pig skin; late fibrosis was not assessed in this study. The values obtained using the chosen endpoint indicate that the RBE is not significantly higher than that seen in any of the early responding tissues for pion doses as low as 2-3 Gy per fraction. The effect of increasing the treatment volume for pion therapy has been assessed using mouse intestine. The results show that for a constant field size, RBE decreases with increasing peak width. However, if peak width is held constant and field size increased, there is evidence for an increased RBE.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pion therapy at TRIUMF. Treatment results for astrocytoma grades 3 and 4: a pilot study.

At TRIUMF, (located on the University of B.C. Campus), 53 patients with supratentorial astrocytoma grades 3 and 4 were treated with pions between 1982 and 1985. A 3-dimensional spot-scanning treatment technique has proven to be practical. The accuracy of the beam alignment system used for treatment was reproducible daily within 2 mm. Low pion flux has hindered optimal beam shaping but this will soon be remedied as flux improves. The overall median survival observed (53 patients) is 262 days from date of first radiation treatment. Younger (less than 49 years) patients have significantly better survival than older (greater than 50 years) patients (p = 0.001). From a base line dose of 40 Gy photons whole brain and 17.5 Gy pion boost, doses were escalated to 33 Gy pions localised to the primary tumour and the median survival improved from 198 to 436 days. Survival curves for patients treated with localised pion techniques to doses above 30 Gy are significantly better than for those treated with schedules of pions mixed with photons (p = 0.04). It appears that optimal pion dose for brain tumours is 33 Gy minimum with a possible maximum of 36 Gy and doses delivered in 15 fractions in 3 weeks. Requirements for future trials are discussed.

Adult↗
PubMed1990

Combination therapy of pions and SPG (Sonifilan, Schizophyllan), a biological response modifier for mouse tumor systems.

Female C3H mice aged 8-10 weeks with transplanted KHT sarcoma or SCCVII tumor were used to investigate the antitumor effect of SPG (Sonifilan, Schizophyllan) alone and in combination with local irradiation of pions with 4 fractions of 400 cGy (total 1600 cGy). Daily doses of 10 mg/kg of SPG were given intramuscularly to the mice bearing KHT sarcoma for 14 consecutive days from day 7, and to mice bearing SCCVII tumor for 20 consecutive days from day 7 and thereafter three times a week for another 2 weeks. The antitumor effect was evaluated by the changes in tumor volume, survival curves, and the number of pulmonary metastatic nodules on the surface of the lungs. SPG failed to exert any antitumor effect and any life-prolonging effect for the KHT sarcoma. As for SCCVII tumor, in the group treated with pions and SPG, tumor growth decreased significantly (p less than 0.01) compared with the group treated with pion only, and life prolonging effect and metastasis-suppressing effect were also observed (p less than 0.04). In conditions of minimal residual disease brought about by pion irradiation, the adjuvant effect of a Biological Response Modifier (BRM) SPG may prove to be a promising method of cancer therapy for some tumors.

Animals↗
PubMed1990

On the biophysical interpretation of the mathematical product of dose and relative biological effectiveness.

The mathematical product of dose and relative biological effectiveness (DR) is commonly used empirically as the 'effective' dose of radiations. It is often interpreted as the equivalent dose of a reference radiation, such that the individual DRs of the radiation components are summed like physical doses in a mixture of radiations with different RBE values. It is shown that such a physical interpretation of DR would be both mathematically and logically inconsistent unless the action of each radiation has a constant RBE value for all end-effects. This is contrary to general experimental findings. Based on the isoeffect biological connotation in the definition of RBE, a biophysical interpretation is being introduced in this paper in which DR is always interpreted with respect to a particular end-effect on which the RBE value is evaluated, somewhat similar to having an extra biological dimension. Hence, only DRs evaluated for the same end-effect can be meaningfully computed together in a mixture. From the empirical results of radiobiological experiments using mixtures of radiations of different qualities, DRs of radiation components are shown to be additive in a mixture just like physical doses. A convenient linear computation framework is, therefore, available for the use of DRs in the empirical calculation of effect of mixtures of radiations of different qualities. The bearing of this biophysical interpretation of DR on radiation protection and treatment planning is discussed.

Biophysical Phenomena↗
PubMed1990

On the use of the pion stopping distribution and the lesion additivity concept for the calculation of effective doses in pion treatment planning.

The large spatial variation in LET, and hence in RBE, is one of the main obstacles in the development of routine treatment planning of charged particle beams. Since the biological effect distribution of plans cannot be realistically measured for each patient, a simple scheme of relating effect to basic empirical physical measurement is required. For the case of a pion beam, the high LET dose distribution is correlated with that of the pion stopping density, which can be indirectly measured using several techniques. A scheme based on this spatial correlation has been developed. In this method, after partitioning the local dose into a high and a low LET fraction, the local effective dose is computed using a simple formula extracted from a recent analysis of radiobiological results for mixtures of radiations of different LET. This simple formula can also be derived from a mechanistic model of mixed radiation action developed using the hypothesis of additivity of common intermediate lesions. In this paper, the concept of spatial correlation between the high LET dose and the pion stars is merged with the concept of lesion additivity for mixed radiation, from which a simple computational scheme is formulated for the calculation of effective doses in the treatment planning of pions. Similar schemes can also be developed for other charged particle beams.

Elementary Particles↗
PubMed1989

Analysis of interaction for mixtures of agents using the linear isobole.

The linear isobole that is commonly used as a reference for the study of interaction is derived from the interaction of an agent with itself. It is shown that the general use of the linear isobole in the study of the combined effects of mixtures of agents implies interaction between the agents whether the dose-effect curves of the agents are the same or not. It is difficult to generalize the interaction between two doses of the same agent to the interaction between two doses of different agents with different action mechanisms without the use of a mechanistic model. Predictions using non-interaction defined as independent action are generally different from those using linear isobole. A simple mechanistic framework based on the concept of common intermediate lesions is introduced in this paper to relate these two methods used for the analysis of synergism and antagonism. In this framework of lesion development, two agents that have no common intermediate lesion in their action will be non-interactive (referred to as independent action). When the two agents share a common intermediate, it is shown that the combined effect will follow the linear isobole (referred to as common action). This simple framework of analysis is applicable to the general study of interaction between two agents with different types of dose-effect curves.

Drug Interactions↗
PubMed1989

Effect of different stopping volumes of clinical pion beams at TRIUMF on the mouse small intestine.

The survival of mouse jejunal crypt cells was measured using a microcolony assay following irradiation with one of three different pion stopping volumes. All treatments were done using the beam spot scanning system developed for clinical therapy at TRIUMF. Treatment volumes were Small, 10 ml of volume using 4 beam spots with a narrow stopping peak; Moderate, 40 ml of volume using 4 beam spots with an extended peak; Large, 1.2 liters of volume using 37 spots with an extended peak. The dose rate fluctuated considerably during treatment because of the scanning procedure. The relative biological effectiveness (RBE) values of pions were 1.11, 1.04, and 1.16 for the small, moderate, and large volumes, respectively. As the width of the stopping peak increased, from the narrow 4-cm peak of the small volume to the 12-cm peak of the moderate volume, the effectiveness of the pion beam decreased. This presumably reflects the low linear energy transfer contribution of the large number of passing pions in the wider stopping peak. The results indicate, however, a greater biological effectiveness for the large volume than for the moderate volume. Even though these fields had stopping peaks of similar width, the field size and dose rate were different. Although the increase in RBE may be partly due to an increased neutron flux from the larger volume, our results suggest that much of this apparent increase could be explained by differences in dose rate as a function of time for pions versus X rays.

Animals↗
PubMed1989

An isoeffect approach to the study of combined effects of mixed radiations--the nonparametric analysis of in vivo data.

The combined effects of mixed radiations can be examined using a system of simple isoeffect relations which are derived from a recent analysis of in vitro results obtained for a variety of radiation mixtures. Similar isoeffect analysis methods have been used for over two decades in studies of the combined action of toxic agents such as drugs and antibiotics. Because of the isoeffect approach, the method is particularly useful for the analysis of ordinal data for which conventional models that are based on parametric dose-effect relations may not be suitable. This is illustrated by applying the method to the analysis of a set of recently published in vivo data using the mouse foot skin reaction system for mixtures of neutrons and X rays. The good agreement between this method and the ordinal data also helps to provide further experimental support for the existence of a class of radiobiological data for which the simple isoeffect relations are valid.

Animals↗
PubMed1988

The combined effects of mixtures of ionizing radiations.

Ionizing radiation is a special group of toxic agents whose general interaction can be calculated. This was demonstrated using a radiation interaction model previously published. In this paper, this model is refined and mathematically reformulated using a unified set of assumptions. It postulates the existence of a common intermediate lesion and the relative action of lesions before, at and after this common stage. General quantitative dose-effect relationships of mixed radiations can be derived from the dose-effect relationships of the components in the mixture.

Animals↗
PubMed1988

Phosphorylation of (Na+ + K+)-ATPase; stimulation and inhibition by substituted and unsubstituted amines.

(1) In view of a previously established stimulation of steady-state phosphorylation of (Na+ + K+)-ATPase by imidazole and its inhibition by tris(hydroxymethyl)aminomethane, the effect of (structure, chemical composition and charge of) a number of primary, secondary and tertiary amines (including imidazole derivatives) has been investigated. (2) Primary amines are predominantly inhibitory and diamines are more inhibitory than monoamines. The strongest inhibition is exerted by ethylenediamine (I50 in 50 mM imidazole = 25 microM, vs. 60 mM for n-propylamine). Increasing the distance between the two amino groups from 3.7 to 8.7 A increases the I50 180-fold. The optimal distance of 3-4 A indicates a similar distance between two ligand(presumably Na+)-binding sites on the enzyme. (3) Screening or substitution of the central N-atom decreases inhibition by the nitrogen compound. Triple substitution by propyl or allyl groups leads to maximal activation, amounting to about 90% of the Na+-activation level. Triethyl substitution gives suboptimal activation and tributyl substitution leads to inhibition. Substitution by polar or negatively charged carboxyl groups diminishes or even abolishes inhibition and also diminishes or abolishes activation. (4) Although occasionally positive charge is not required for inhibition, it is prerequisite for activation. Within certain families of compounds (e.g., ethylenediamine and imidazole derivatives) inhibition or activation increases with pKa, hence with positive charge. (5) The above data are interpreted in terms of inhibition, which is competitive to Na+, being governed by Coulomb interaction. Activation, on the other hand, is predominantly determined by lipophilic (van der Waals or pi-pi electron) interactions, excluding water from the phosphorylation site, hence decreasing phosphoenzyme hydrolysis and increasing the phosphoenzyme level. The requirement of charge (though hidden by substitution) implies weak additional electrostatic interaction.

Adenosine Triphosphate↗
PubMed1988

On the general validity of linear summation of dose equivalents for mixed radiations.

The current definition of dose equivalent for a mixture of radiations used in radiation protection implies some interaction between the radiations. This interaction cannot be derived from the existing biophysical models. A simple concept of interaction is introduced based on the postulate that in the chain of radiation inactivation events, there exists an intermediate stage where different initial lesions, produced by different radiations, become functionally indistinguishable. Hence, they are additive thereafter to produce the same end point observed. It can be shown that the definition of dose equivalent and the definition of average quality factors for mixed radiations can be derived from this concept. Furthermore, this simple concept can be shown to be consistent with many of the published experimental results in radiobiology using mixed radiations. The lesion additivity concept helps to provide both theoretical and experimental support for the otherwise arbitrary definitions of dose equivalent and average quality factor.

Cell Survival↗
PubMed1987

The interaction of radiations of different LET.

Experimental data for mixed radiation of different LET are analysed using an isobologram approach and are shown to be consistent with the special case of 'zero interaction' in a general formulation of the effect of a combination of agents proposed by Berenbaum. This zero interaction is defined in the same sense as interaction between the lesions produced by the same radiation. This makes analysis and predictions of mixed radiation results particularly straightforward. The zero-interaction formula can be mathematically derived from a simple model of mixed radiation called the lesion additivity model using the assumption that different early lesions produced in the radiation mixture can gradually develop into an indistinguishable intermediate state and hence become additive to produce the same end point. The model is shown to be applicable to irradiation under both hypoxic and oxygenated conditions and hence is extended to the use of hypoxic cell sensitisers.

Dose-Response Relationship, Radiation↗