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R M Sutherland

Publications and source records attributed to R M Sutherland.

202 records · Page 12Linked to original sources
PubMedDate not supplied

In vitro hypoxic cytotoxicity of nitroimidazoles: uptake and cell cycle phase specificity.

The hypoxic cytotoxicity of four different 2-nitroimidazoles of similar electron affinities but different lipophilicities was compared using EMT6/Ro mouse mammary tumor cells in exponential growth phase in severely (less than 20 ppm) hypoxic conditions. The relative cytotoxicities were misonidazole (MISO) = desmethylmisonidazole (9963) greater than SR-2508 much greater than SR-2555 indicating that the compounds with the lowest lipophilicity were less cytotoxic. The rates of uptake of these compounds were MISO greater than 9963 greater than SR-2508 = SR-2555. These data together with comparisons of the amounts of cell-associated compounds indicate that the similarity in toxicity of MISO and 9963 can be related to a general similarity in their pharmacokinetics, but that other unknown factors must be considered to explain the relative toxicity of SR-2508 and SR-2555. In other experiments, EMT6/Ro cells synchronized using centrifugal elutriation were most sensitive in hypoxia to MISO at the late G1--early S phase of the cell cycle. These data indicate the importance of considering cellular and subcellular distribution of these nitroimidazoles as well as possible cell cycle specificity for cytotoxicity in interpreting relative effectiveness of different compounds in responses of mixed populations of cells in cultures or tumors.

Animals↗
PubMedDate not supplied

Dosimetry models for radioimmunotherapy.

Tumor therapy using radiolabeled antibodies presents a challenging problem in absorbed dose determination. The purpose of this study is to evaluate the effect of tumor size on the absorbed dose distribution from beta-emitters when the radiolabeled antibody is not uniformly distributed throughout the tumor. Two theoretical dosimetry models are constructed, one for nonvascularized micrometastases and the other for vascularized tumors. All calculations assume no penetration of radionuclide into the tumor. These are compared to an even distribution of radionuclide throughout the tumor. In micrometastases of 1-mm diameter or less, emitters of low energy such as 131I give higher dose rates than emitters of higher energy because less energy is lost outside the target volume. However, even with 131I, a significant proportion of the energy is not absorbed in the tumor and, as a result, the concentration of radionuclide necessary for a therapeutic radiation dose becomes higher as the tumor diameter gets smaller. Because it may be impossible to achieve these concentrations in very small tumors (less than 0.5-mm diameter), alpha-emitters may be useful in combination with beta-emitters for therapy of micrometastatic disease. In vascularized tumors, higher energy emitters such as 90Y yield higher doses because of overlapping dose distributions from multiple vascular sources. This also produces a more even dose distribution across a tumor, even when there is poor penetration of the radiolabeled antibody. Thus tumor size, antibody penetration, and tumor vascularity all influence the choice of radionuclide and, depending on the circumstances, alpha-emitters, low-energy beta-emitters, high-energy beta-emitters, or some combination of the three may be most efficacious.

Antibodies↗
PubMedDate not supplied

Radiobiology of radiolabeled antibody therapy as applied to tumor dosimetry.

This paper reviews the radiobiological aspects of radioimmunotherapy (RIT) with radiolabeled antibodies, including comparisons between RIT and external beam irradiation. The effectiveness of cell killing by radiation decreases with the dose rate and the rate of decrease is determined by the size of the shoulder on the radiation survival curve. Tumors with poor repair capabilities exhibit less of a dose rate effect than tumors with good repair capabilities. Continued tumor cell proliferation during treatment occurs at very low dose rates and can contribute to the reduced effectiveness of low dose rate radiation. Toxicity to normal tissues will determine the total dose of radiolabeled antibody that can be given and this will be influenced by the choice of both the radionuclide and the antibody. The reported enhanced effectiveness of RIT may be due to multiple factors including selective targeting of cells responsible for tumor volume doubling, tumor surface binding rather than homogeneous binding throughout the tumor volume, targeting of the tumor vasculature, or block of cell cycle progression in G2. During RIT, there is less time for reoxygenation of hypoxic tumor cells than during a course of conventional external beam radiotherapy. It has not yet been determined whether this will have a detrimental effect on RIT. Probably the most important factor in the success of RIT is dose heterogeneity. Any viable portion of a tumor that is not targeted and does not receive a significant radiation dose will potentially lead to treatment failure, no matter how high the dose received by the remainder of the tumor. Comparisons between RIT and external beam radiation have shown a wide range of relative efficacy. Tumors most likely to respond to RIT are tumors with poor repair capabilities, tumors that are susceptible to blockage in radiosensitive phases of the cell cycle, tumors that reoxygenate rapidly, and tumors that express the relevant antigen homogeneously. From a radiobiological perspective, it appears that RIT alone is unlikely to cure many tumors and that combination with other treatment modalities will be essential.

Cell Hypoxia↗