Gerry Blekkenhorst

The clinical and biochemical features of variegate porphyria. An analysis of 300 cases studied at Groote Schuur Hospital, Cape Town

Abstract The main clinical features of 300 cases of VP in respect of their racial and sex incidence and age and mode of presentation, as well as their diagnostic biochemical features have been presented. The abundance of clinical material made it possible to undertake 7 special studies. The 2 most important of these were: (1) the acute attack and its electrolyte disorder, a very high incidence of severe hyponatremia, hypochloremia and azotemia, and a lesser but substantial incidence of alkalosis and hypokalemia. The causes of the electrolyte disorder have been extensively investigated. (2) The structure of the porphyrin peptides and their diagnostic significance have been defined.

The effect of bleeding and iron administration on the development of hexachlorobenzene-induced rat porphyria

Abstract 1. 1. Iron overload and iron depletion respectively potentiated and diminished the porphyrinogenic effect of hexachlorobenzene in rats, as assessed by hepatic, renal and colonie activity of uroporphyrinogen decarboxylase and by urinary and faecal porphyrin excretion. 2. 2. In the early phase of hexachlorobenzene intoxication the rat undergoes a definite porphyric phase different from the porphyria cutanea tarda-like phase which occurs later. 3. 3. Preliminary indications are that faecal and urinary uroporphyrin excretion can be correlated with colonie and renal uroporphyrinogen decarboxylase activity respectively.

The treatment of tumors by the induction of anemia and irradiation in hyperbaric oxygen

Because increased effects have been achieved when murine tumors are irradiated after a period of hypoxia and because of anecdotal clinical experiences of an improved result after irradiation of previously anemic patients in hyperbaric oxygen, the relationship between irradiation and increased survival was investigated in seventy‐two patients with advanced head and neck or cervical cancer. Anemia was achieved by means of a two‐stage isovolemic venesection maintained for seventy‐two hours, hemoglobin was returned to a normal level, and treatment in hyperbaric oxygen was started. Marked tumor shrinkage after the induction of anemia and before radiotherapy was seen and was probably disease, site, and hemoglobin level related. As a result, a possible new approach to cancer therapy is suggested. After completion of therapy, the 1‐year disease‐free survival for patients with head and neck and cervical cancer was not improved, but the 21‐month survival for cervical cancer was improved. Further studies are strongly urged.

A preliminary report on a new perspective in clinical radiation sensitization and hypoxic cell chemotherapy

The actions of misonidazole as a radiation sensitizer, hypoxic cytotoxic, and metabolic inhibitor are all concentration‐dependent, and the commonly prescribed oral dose (I2 g/m2) appears to be inadequate. The drug has, therefore, been given interstitially in solid form, when local tissue doses of the order of tens of millimolar are attained, to four patients, all with advanced disease. In the three cases (two squamous carcinomas and a malignant melanoma) in whom the drug concentration was considered to be adequate, a beneficial effect was obtained, which, in two instances, was associated with doses of radiation of 6 and 8 Gy, respectively. This approach has a wide potential application in cancer therapy.

Drug induced acute porphyric episodes in rats

Abstract 1. 1. Chronic treatment with 0.07% hexachlorobenzene produced a prolonged intermediate porphyric stage in rats very different from the symptomatic porphyria-like syndrome produced by higher doses and longer treatment. 2. 2. Administration of further porphyrinogenic agents to rats in the intermediate porphyric stage induced acute episodes biochemically very similar to the human acute porphyric attack. 3. 3. Few of the excess porphyrins excreted by the rats were of hepatic origin. Faecal porphyrins apparently were synthesized in the intestinal tract, whilst urinary porphyrins originated mainly in the kidney, even during the acute episode.

In Vivo Radiosensitization by Diethyldithiocarbamate

Diethyldithiocarbamate (DDC) has been suggested to have both radiosensitizing (due to superoxide dismutase (SOD) inhibition) and radioprotective properties. We have studied the activity of SOD up to 24 h after intratumoral administration of 50, 100, 150, and 300 mg/kg DDC in 3-methylcholanthrene-induced tumors in BALB/c mice. Maximal inhibition of SOD (8% of control) was obtained 1 h after administration of 100 mg/kg DDC. Tumor response to DDC and X irradiation was assessed using a tumor growth-delay assay, after 11 Gy 100-kVp X rays given up to 24 h after DDC administration. Radiation-induced tumor growth delay (7.11 +/- 1.76 days) was enhanced only when tumors were irradiated 2-4 h after 50 mg/kg DDC. When higher doses of DDC were used, tumor cure was noted when DDC was injected 1-6 h before irradiation. We suggest our findings are consistent with radiosensitization being due to SOD inhibition, but that if insufficient time is allowed between DDC injection and irradiation, the sensitization is masked by a radioprotective effect. We believe that further investigations as to the therapeutic potential of DDC in human patients with cancer are warranted.

The Effect of Irradiation in Air or in Hyperbaric Oxygen on the Fib/T Tumor in WHT Mice Pretreated with a Hypoxic Gas Mixture

The effect of exposing WHT mice bearing the Fib/T tumor to a low-oxygen environment (8, 10, and 15% oxygen) for 48 h or 72 h before irradiation was compared, using an in vitro colony-forming excision assay, to the effect obtained when mice were pretreated with air. The response of the Fib/T tumor to radiation delivered in air was improved both by a 48-h and by a 72-h exposure of the animals to 8, 10, and 15% oxygen. However, the greatest tumor sensitization was achieved when mice were kept in 8% oxygen for 48 h before irradiation. These results are interpreted and discussed in relation to increases in the 2,3-DPG concentration, which were shown to occur when mice were exposed to a reduced oxygen environment. The relative importance of two models proposed to explain these findings is assessed. If mice pretreated with air were irradiated in hyperbaric oxygen, a similar tumor response was observed compared to that when mice were exposed to 8% oxygen for 48 h and then irradiated in air.

Tumor blood flow measurements using coincidence counting on patients treated with neutrons

PURPOSE The purpose of this work was to measure blood flow in tumors using a coincidence counting technique on patients undergoing treatment with neutrons. METHODS AND MATERIALS The half-time, Tw, for the washout of 15O from neutron-activated tumors was measured with two 10 cm NaI(Tl) crystals coupled to a PC-based coincidence counting system. Blood flow measurements were made in 33 patients, 19 of whom had cancers of the head and neck region, 6 had breast cancer, 5 had sarcomas, and 3 patients had mesotheliomas. RESULTS Blood flow as indicated by Tw of mobile 15O formed by neutron activation could be readily determined in tumors of patients undergoing neutron radiotherapy. The general reduction in the value for Tw was noted towards the end of treatment and did not seem to be dependent on the initial tumor volume. There was a tendency for larger lesions to be associated with longer half-times of 15O washout. CONCLUSION It appears possible to obtain a reasonable estimate of tumor blood flow using a simple coincidence counting technique. In view of the large variation in blood flow between tumors, it did not appear to be possible to identify potentially hypoxic tumors that would respond to neutron therapy.

Interstitial misonidazole clinical experience in advanced mouth cancer

In an attempt to obtain full radiosensitisation and avoid dose-limiting neurotoxicity, a needle has been specially developed for the injection of misonidazole pellets into tumours. The methods of production and insertion of the pellets are described. Thirteen advanced, untreated squamous carcinomas of the mouth were injected and then irradiated to tolerance. Twelve out of 13 implanted lesions had completely regressed at the end of treatment but only six remained healed after 1 year.

Studies on erythrocyte porphobilinogen deaminase and uroporphyrinogen cosynthetase in Porphyria cutanea tarda

Abstract 1. 1. Erythrocyte porphobilinogen deaminase and uroporphyrinogen cosynthetase were determined using thin-layer chromatography and high-performance liquid chromatography respectively to quantitate reaction products. 2. 2. No difference was observed in the activity of erythrocyte porphobilinogen deaminase between normals and patients with porphyria cutanea tarda, but levels were significantly increased in liver disease, and significantly decreased in chronic renal failure. 3. 3. No evidence of different patterns of uroporphyrin isomer generation was found between haemolysates from controls and from patients with sporadic porphyria cutanea tarda, implying the absence of a possibly inherited defect in uroporphyrinogen cosynthetase.