Photoinactivation of Chinese hamster cells by hematoporphyrin derivative and red light.
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Animals↗
Biomedical subjects
C J Gomer
Publications and source records attributed to C J Gomer.
Initial United States clinical and pharmacologic evaluation of misonidazole (Ro-07-0582), an hypoxic cell radiosensitizer.
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Administration, Oral↗
Relationship between misonidazole toxicity and core temperature in C3H mice.
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Animals↗
Determination of [3H]- and [14C]hematoporphyrin derivative distribution in malignant and normal tissue.
The synthesis and tissue-localizing ability of [14C]- and [3H]hematoporphyrin derivative (HPD) in mice have been described. Tissue levels and distributions were the same for both radioactive compounds, indicating that in vivo tritium exchange did not occur with [3H]HPD. The amount of [14C]HPD or [3H]HPD which localized in the transplanted tumor tissue of mice at various times following i.p. injection (10 mg/kg) was higher than in skin or muscle tissue but was less than in liver, kidney, or spleen tissue. These results tend to disprove the generalization that HPD accumulates in malignant tissue to a higher degree than in all normal tissue. It is also reported that gross visualization of porphyrin fluorescence cannot be correlated with actual tissue concentrations of the dye.
Animals↗
The demonstration of in vivo misonidazole tumour toxicity using post radiation hypoxia.
The cytotoxic effect of the radiosensitizer misonidazole on hypoxic tumour cells in vivo has been studied. Using standard procedures of large single doses of X-ray (30 Gy) followed by 1.0 mg/g misonidazole, no significant cytotoxicity (measured by tumour regrowth) could be observed. In contrast, when utilizing post radiation hypoxia (3 h of 7% oxygen breathing) in conjunction with post radiation misonidazole, an increased amount of direct drug toxicity was demonstrated. The use of this acute hypoxia treatment may prove to be a useful tool for measuring various in vivo radiobiological responses.
Animals↗
The hypoxic cell sensitizer programme in the United States.
The initial results of a Phase I evaluation of misonidazole in the U.S.A. are described, as well as the U.S. National Cancer Institute programme for radiosensitizer development. A total of 12 patients have been given 1--6 doses of 1--2 g/m2. Serum levels ranged from 25--87 microgram/ml at 4--6 h. One patient has developed mild peripheral neuropathy. Urinary excretion was chiefly of a demethylated metabolite as measured by HPLC assay.
Aged↗
Identification of singlet oxygen as the cytotoxic agent in photoinactivation of a murine tumor.
Singlet oxygen, a metastable state of normal triplet oxygen, has been identified as the cytotoxic agent that is probably responsible for in vitro inactivation of TA-3 mouse mammary carcinoma cells following incorporation of hematoporphyrin and exposure to red light. This photodynamic inactivation can be completely inhibited by intracellular 1,3-diphenylisobenzofuran. This very efficient singlet oxygen trap is not toxic to the cells nor does it absorb the light responsible for hematoporphyrin activation. We have found that the singlet oxygen-trapping product, o-dibenzoylbenzene, is formed nearly quantitatively intracellularly when both the furan and hematoporphyrin are present during illumination but not when only the furan is present during illumination. The protective effect against photodynamic inactivation of the TA-3 cells afforded by 1,3-diphenylisobenzofuran coupled with the nearly quantitative formation of the singlet oxygen-trapping product indicates that singlet oxygen is the probable agent responsible for toxicity in this system.
Animals↗
Energetics and efficiency of photoinactivation of murine tumor cells containing hematoporphyrin.
Hematoporphryrin derivative at an intracellular concentration in TA-3 mouse mammary carcinoma cells of 0.6 or 0.9 mM required input of 3.0 X 3.6 X 10(9) quanta/cell of red light (620 nm) to achieve a 90% kill. At an intracellular concentration of 1.2 mM, this light requirement drops to 1.5 X 10(9)quanta/cell. The energy for this photodynamic process is about 100 times higher than that required for ionizing radiation to achieve the same level of kill for these cells. The quantum yield for singlet oxygen formation (the cytotoxic agent in most photodynamic processes) from hematoporphyrin derivative is 0.75 +/- 0.07 in ethanol but only 0.16 +/- 0.07 within TA-3 cells, indicating possible intracellular complexing and quenching.
Animals↗
Tissue concentrations of doxorubicin in animal models with engrafted intraocular tumours.
The role of chemotherapy in the management of retinoblastoma remains unclear. In order to evaluate the responsiveness to conventional or experimental agents, a xenograft model had been developed, where human retinoblastoma is heterotransplanted to the anterior chambers of nude mouse eyes. Because doxorubicin had been found to be ineffective in therapeutic studies utilizing the model, experiments were conducted to evaluate the concentration of the drug in tissues, including intraocular engrafted tumour. The presence of doxorubicin was demonstrated in xenograft containing mouse eyes as well as in tumours of a comparable rabbit model. Distribution in extraocular tissues was consistent with previously published data. It is concluded that failure of response to doxorubicin in the xenograft model is not explained by lack of tumour penetration by the drug.
Animals↗