Photoradiation therapy causing selective tumor kill in a rat glioma model

We evaluated the effect of photoradiation therapy using the photosensitizer, hematoporphyrin derivative (HpD), and the argon-pumped rhodamine dye laser tuned to 630 nm in the rat C6 glioma model. Animal models of cerebral glioma were established by implanting 10(6) C6 glioma cells in adult Wistar rats, and craniotomies were performed on normal and tumor-bearing animals. HpD in doses of up to 80 mg/kg followed by craniotomy resulted in no damage to the normal brain, and laser light at doses of up to 1200 joules/cm2 without the prior administration of HpD produced no significant damage if the craniotomy site was irrigated with normal saline to prevent a temperature rise. Photoradiation caused no brain necrosis in non-tumor bearing animals if less than 20 mg of HpD per kg and 200 joules of red light per cm2 were used. At higher doses of HpD and light, cerebral necrosis did occur. The depth of necrosis depended on the dose of both HpD and light. Treatment with 40 mg of HpD per kg and 400 joules of light per cm2 resulted in cerebral necrosis in 50% of the treated animals. The mean depth of brain necrosis was 1.3 mm. Selective kill of a cerebral glioma with sparing of the normal brain was achieved with photoradiation therapy at doses of HpD of less than 20 mg/kg and light doses of less than 200 joules/cm2. At these doses, the mean depth of tumor kill was 4.5 mm. In 2 of 10 animals, the depth of tumor destruction was more than 6 mm.(ABSTRACT TRUNCATED AT 250 WORDS)     

Photoradiation therapy of bladder tumors

Photoradiation therapy, in which hematoporphyrin derivative is activated by an argon-dye laser, was performed on 46 superficial bladder tumors in 9 patients. A fluorospectrophotometric study of biopsies from these tumors and normal mucosa revealed preferential hematoporphyrin derivative localization in malignant tissues. The tumor response was confirmed ultrasonographically in 36 stages Ta to Tl tumors. Treatment with 100 to 250 J./cm.2 obtained complete remission in 5 of 6 patients with tumors 1 cm. in size or less. For those with tumors up to 2 cm. in size the light intensity should be 300 mw./cm.2 for 5 to 10 minutes or more and the accumulated energy intensity of light dose should be 100 J./cm.2 or more. No patient with tumors more than 2 cm. in size had a complete remission.     

Evaluation of megadose vitamin therapy in an experimental brain tumor

A mixture of vitamins C and B₁₂ in high dosage, which has been reported to eradicate ascites tumors in rats, was tested for its antineoplastic effect against the L9 glioma in Fisher CDF strain rats. No difference in survival time between animals receiving the vitamin mixture and controls could be demonstrated. Possible reasons for the different response to therapy in the two experimental tumor systems are discussed.     

Photoradiation therapy: current status and applications in the treatment of brain tumors

Photoradiation therapy is achieved when a photosensitizing drug is activated by light to form products that are lethal to tumor cells. The most commonly used drug is hematoporphyrin derivative, which is preferentially taken up and retained by malignant tissue. Photoactivation is usually produced by using a dye laser tuned at 630 nm (red light). The primary mechanism of neoplastic cell damage in photoradiation therapy involves the production of free radicals formed during illumination of hematoporphyrin derivative by light of this wavelength. The treatment would seem to damage first the tumor cell membrane, then the cytoplasmic inclusions, and finally the nucleus. Photoradiation therapy has been quite effective in the treatment of superficial malignancies, especially in skin, breast, eye, bladder, bronchus, and stomach. Experience with brain tumors is still limited. Important unresolved problems in the application of photoradiation therapy to gliomas include relative uptake of hematoporphyrin derivative into the tumor, limited light penetration of the tissue, local heating, and damage induced in normal brain by photoradiation therapy.     

Chemotherapy for experimental subarachnoid dissemination model of brain tumor

Chemotherapy was applied for experimental subarachnoid dissemination model of brain tumor which was established in male Wister-SPF (SLC) rats inoculated intracisternally with 2 X 10(5) C6 rat glioma cells. Nontreated animals died about 24 days after inoculation. Autopsy findings of the animals showed localized or multifocal invasion of the tumor on leptomeninges in cisterna magna, and partially infiltration into the parenchyma of the cerebellum and medulla oblongata. Three days after inoculation, the tumor deposition and proliferation already occurred. Several tumor cell layers were found in the subarachnoid space over the cerebellomedullary surface. Tumor bearing animals were at first treated by single agent. These are ACNU administered intraperitoneally, methotrexate administered intracisternally, and OK-432 administered intraperitoneally. In the next stage, combination of these drugs was applied. ACNU, 3 mg/kg i. p., on Day 3, was effective in elongation of median survival time by 23.6%, statistically significant (P less than 0.02). Methotrexate, 0.25 mg/kg i.th., on Day 3, was also effective in elongation of median survival time by 8.4%, statistically significant (P less than 0.05). OK-432, 0.1 KE/kg i. p., daily, 14 times, from Day 3 to Day 16, was ineffective in elongation of median survival time. Combination of ACNU, methotrexate and OK-432, in the same schedule as described above, produced the longest median survival time of 42.4%, statistically significant (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Photoradiation therapy of endobronchial lung cancers employing the photodynamic action of hematoporphyrin derivative

Thirty-five patients with tumors within the tracheobronchial tree were treated with photoradiation therapy (PRT) employing the photodynamic action of hematoporphyrin derivative (HPD). An effective protocol has been developed consisting of 3.0 mg/kg HPD given intravenously 72 hours prior to the bronchoscopic illumination of the endobronchial tumor sites with red light (630 nm) from an argon pumped dye laser. Light applicators were developed that provided surface (area) and insertion (volume) illumination of tumor masses. Average light dosages of 100 J/cm2 and 200 J/cm were used for surface and insertion illumination, respectively. Delivery rates were 200 mW/cm2 and 400 mW/cm. There was no immediate visible effect such as coagulation or charring noted. All malignant endobronchial tumors responded. Tumors included primary and metastatic lesions of various histologic types. Response was complete for tumor within the bronchus after one treatment in 80% of instances. The remaining cases required two treatments to obtain a complete response due to the extensive length of bronchus involved or because multiple sites were present. A complete response, that is, the full opening up of the lumen to the bronchial wall, was accomplished in all but one instance. Atelectatic lungs or lobes were re-expanded and reaerated. Dyspnea and cough became significantly less. The follow-up achieved to date indicates improvement in symptoms, activity level, and the return to work in a significant number of cases.     

Detection of experimental brain tumor in rat by computed tomography

The feasibility of the use of computerized tomographic (CT) scanning for detecting an experimental brain tumor in rats was evaluated. Tumors were induced in newborn rats by intracerebral inoculation of Rous sarcoma virus. At varying times contrast-enhanced scans were obtained on an Ohio Nuclear 2010 scanner, the brains examined, and the findings at autopsy correlated with the CT findings. Five tumors were demonstrated by CT scans and their presence confirmed at autopsy. Four small tumors were not detected by CT scans. In 1 animal, multiple tumors were demonstrated by a CT scan, and in another a large cyst was correctly diagnosed. It is concluded that the technology currently available can be used to identify some tumor-bearing animals and should be useful for following the change in size of tumors in response to therapy. Further improvements in scanner resolution should make this technique more useful for animal research.     

Hypertonic saline ameliorates cerebral edema associated with experimental brain tumor

Cerebral edema commonly accompanies brain tumors and frequently leads to lethal intracranial compartmental shifts and elevated intracranial pressure. Therapeutic modalities for tumor-associated cerebral edema include diuretics, osmotherapy, and corticosteroids. Recently, hypertonic saline (HS) has received attention as an osmotic agent in the treatment of cerebral edema from diverse causes. The effects of continuous HS infusion in brain tumor-associated edema have not been previously reported. Therefore, we tested the hypothesis that HS given as a continuous intravenous infusion ameliorates tumor-associated edema in a rat model of brain tumor. 9L gliosarcoma, propagated as a solid flank tumor, was implanted intracranially over the left hemisphere in adult female Fischer 344 rats (180-220 g). On day 11 after implantation, rats were divided in a blinded, randomized fashion into groups that received no treatment or continuous infusion of 0.9% saline (NS) (0.3 mL/h) and in a subsequent series that included NS + intravenous furosemide 2.5 mg/kg every six hours, NS + intravenous mannitol 2.5 g/kg every six hours, or continuous infusion 7.5% HS (chloride:acetate 50:50) (0.3 mL/h). Hemispheric water content ipsilateral (IH) and contralateral to tumor implantation was determined at day 13 by wet-to-dry weight ratio after 48 hours of therapy. Ipsilateral hemispheric water content (mean +/- SEM) was significantly increased in rats with intracranial tumor on day 11 (80.3 +/- 0.5%) (n = 7) and day 13 (81.4 +/- 0.3%) (n = 10), as compared to naive weight-matched rats without tumor implant (79.3 +/- 0.1%) (n = 13) (P <.05). After 48 hours of treatment, IH water content was attenuated with continuous HS (n = 15) (79.3 +/- 0.2%), mannitol (n = 14) (80.1 +/- 0.2%), and furosemide (n = 15) (79.9 +/- 0.2%) as compared to NS (n = 7) (80.8 +/- 0.5%). Continuous HS infusion attenuated cerebral edema in the affected hemisphere as well as the contralateral noninjured hemisphere to a larger extent than was observed with furosemide or mannitol. These findings suggest a potential new treatment strategy for tumor-associated cerebral edema.     

Contrasting effects of dopamine therapy in experimental brain injury.

Management of cerebral perfusion pressure (CPP) is thought to be important for the treatment of traumatic brain injury (TBI). Vasopressors have been advocated as a method of increasing mean arterial blood pressure (mABP) and cerebral perfusion pressure (CPP) in the face of rising intracranial pressure (ICP). There are unresolved issues and theoretical risks about this therapy. This study therefore examined the effects of dopamine on physiological and MRI/MRS parameters in (1) a rodent model of rapidly rising intracranial pressure, caused by diffuse injury with secondary insult and (2) a model of cortical contusion. Dopamine was capable of restoring CPP in the model of rapidly rising ICP. This CPP restoration was associated with a partial restoration of CBF. Two profiles of change in the Apparent Diffusion Coefficient of water (ADCw) were seen; one in which ADCw recovered to baseline, and one in which ADCw remained persistently low. Dopamine did not alter these profiles. MRI assessed tissue water content was increased four hours after injury and dopamine increased cerebral water content in both subgroups of injury; significantly in the group with a persistently low ADCw (p < 0.01). In contusional injury, dopamine significantly worsened edema in both the ipsi- and contralateral hippocampus and temporal cortex. This occurred in the absence of ADCw changes, except in the contralateral hippocampus, where both water content and ADCw values rose with treatment, suggesting extracellular accumulation of water. In conclusion, although dopamine is capable of partially restoring CBF after injury, situations exist in which dopamine therapy worsens the swelling process. It is possible therefore that subgroups of patients exist who experience adverse effects of vasopressor treatment, and consequently the effects of vasopressor therapy in the clinical setting need to be more carefully evaluated.     

Resuscitation from experimental traumatic brain injury by magnolol therapy

BackgroundThe purpose of the present study was to determine whether magnolol, a free radical scavenger, mitigates the deleterious effects of traumatic brain injury (TBI).Material and methodsTraumatic brain injuries were induced in anesthetized male Sprague-Dawley rats using fluid percussion, and the rats were divided into groups treated with magnolol (2 mg/kg, intravenously) or vehicle. A group of rats that did not undergo TBI induction was also studied as controls. Biomarkers of TBI, including glycerol and 2,3-dihydroxybenzoic acid, were evaluated by microdialysis. Infraction volume, extent of neuronal apoptosis, and antiapoptosis factor transforming growth factor β1 (TGF-β1) were also measured. Functional outcomes were assessed by motor assays.ResultsCompared with the rats without TBI, the animals with TBI exhibited higher hippocampal glycerol and 2,3-dihydroxybenzoic acid. Relative to the vehicle-treated group, the magnolol-treated group showed decreased hippocampal levels of glycerol and hydroxyl radical levels. The magnolol-treated rats also exhibited decreased cerebral infarction volume and neuronal apoptosis and increased antiapoptosis-associated factor TGF-β1 expression. These effects were translated into improved motor function post TBI.ConclusionsOur results suggest that intravenous magnolol injection mitigates the deleterious effects of TBI in rats based on its potent free radical scavenging capability, and the mechanism of anti–neuronal apoptosis is partly due to an increase in TGF-β1 expression in the ischemic cortex.     

Interferon therapy for brain tumor patients (author's transl)

Nine cases of recurrent and metastatic brain tumors were treated by Hu-IFN-alpha. It was given intramuscularly and singly to those who finished the usual treatments of surgical removal and 60Co irradiation more than 6 months before, to exclude their effects on tumors. They were divided into 2 groups of small dosage (fifty thousands units weekly) and large dosage (3 million units every other day). The total dosage of IFN varied from about 2 million units for the small dosage group to 264 million units for the large dosage group. No side effects were noted. In two cases of six which were followed up over 4 months, the tumors regressed about 50% on serial CT. However, IFN was not effective on the tumors which had already showed a rapid growth before IFN administration. Almost all the patients showed improvements in their general condition, PPD and PHA skin test, peripheral lymphocyte counts and natural killer cell activities.     

Selective change of blood flow in experimental brain tumor with induced hypertension

Blood flow within tumors is important from the standpoint of malignant tumor chemotherapy. It is known that the degree of tissue penetration of lipid-soluble anticancer agents depends on the amount of blood flow within the brain tumor. We investigated regional cerebral blood flow in rats with brain tumors. As compared with that of normal brain, the blood flow within the tumor was low and became significantly increased by inducing a hypertensive condition. These data suggest that the combination of anticancer agent and hypertensive drug is of value to enhance the effects of chemotherapy of brain tumor.     

Two cases of recurrent brain tumor during GH replacement therapy]

Two cases of patients with recurrent brain tumor are presented. Each of them received growth hormone (GH) replacement therapy for growth failure secondary to cranial irradiation. The first case is that of a 10-year-old girl who was treated with a combination of surgical resection, radiotherapy and chemotherapy for cerebellar medulloblastoma at 1 y.o. At the age of 9, 10 month after the beginning of GH replacement therapy, she complained of headache. This was due to shunt malfunction when CSF cytology was class V. It revealed that there was recurrence of medulloblastoma. The second case is that of a 14-year-old girl who was treated with a combination of surgical resection, radiotherapy and chemotherapy for suprasellar germinoma at the age of 10. This tumor completely disappeared after these procedures. For her growth failure, we started GH replacement therapy and after 1 year, she complained of lt. leg pain due to tibial and pelvic bone metastasis. In medical literature, we found 15 recurrent brain tumors during GH replacement therapy. These include our 2 cases, and 9 cases in which there was recurrence within 1 year. Recently, receptors for some somatomedins have been found in brain tumors. Although these numbers are too small for us to arrive at conclusions, we think it is possible that there are some mechanisms connecting GH replacement therapy and recurrence of certain brain tumors.