Chemotherapy Of Malignant Gliomas Research Articles

Antitumor effect and peritumoral brain edema formation in relation to MX2, ACNU, and doxorubicin therapy: A comparative analysis using rodent models of gliomas

The potential antitumor effect of MX2, a new lipophilic morpholino anthracycline, was compared with those of ACNU or doxorubicin (DOX) using two different rodent glioma models. A mouse subcutaneous glioma model (203 glioma) was used to measure the effect of each drug on reducing the glioma size and a rat 9L intracerebral glioma model (9L glioma) was used to assess the antitumor effect on survival rate in a clinically similar fashion. Treatment with ACNU inhibited tumor growth by 94.6% ip ˂ 0.0001) and complete regression of the tumor was observed in 3 of 25 (12.0%) of the ACNU-treated cases. Tumor growth was inhibited by 32.4% with DOX despite a tendency (p˂0.16) and by 59.4% with MX-2 7p ˂ 0.001); neither of these drugs resulted in complete tumor regression. In the intracerebral glioma rats, only ACNU tended to ameliorate survival rate, but there was no statistical significance. These results suggest that ACNU has the most potent effect but MX2 can be an option for chemotherapy of malignant gliomas. Interestingly, all three drugs significantly elevated the brain water content on both the ipsilateral and contralateral sides of the tumor, although they did not induce brain edema in the normal rat brains. Careful management of brain edema might be required regardless of the drug used during chemotherapy to maximize the prognosis of glioma patients. [Neurol Res 2000; 22: 819-824]

Failure of taxol-based combination chemotherapy for malignant glioma cannot be overcome by G2/M checkpoint abrogators or altering the p53 status.

In an effort to develop more effective forms of adjuvant chemotherapy for malignant brain tumors, we sought to develop a taxol-based combination chemotherapy regimen for glioma cell lines in vitro. Here, we report that coexposure of LN-229 or T98G glioma cells to taxol and either doxorubicin, camptothecin, cytarabine, or VM26 resulted in antagonistic effects rather than additive or synergistic cytotoxicity. There were no interactions of taxol with the effects of carmustine (BCNU) or vincristine. Antagonism was more prominent in cytotoxic cell death assays than in clonogenic cell death assays and was not overcome by G2/M checkpoint abrogators such as caffeine or pentoxyfilline. Ectopic expression of mutant and wild-type p53val135 attenuated taxol cytotoxicity in both T98G cells, which are mutant for p53, and LN-229 cells, which exhibit functional wild-type p53 activity. Interestingly, wild-type p53val135 abrogated the taxol-imposed G2/M arrest in both cell lines. However, wild-type p53val135 did not promote glioma cell killing by combinations of taxol and any of the other drugs. Further, an analysis of a panel of 12 human glioma cell lines revealed no relationship between genetic or functional p53 status and taxol sensitivity. In summary, combination either with other chemotherapy drugs, with abrogators of the G2/M checkpoint, with wild-type p53 gene transfer was not a promising approach for a taxol-based combination chemotherapy regimen in malignant glioma.

Gemcitabine cytotoxicity of human malignant glioma cells: modulation by antioxidants, BCL-2 and dexamethasone

Gemcitabine is a novel antimetabolite drug that acts by multiple mechanisms, including inhibition of ribonucleoside diphosphate reductase, of dCMP deaminase and of dCTP incorporation into DNA and RNA. Here, we report that gemcitabine induces cytotoxic and clonogenic death of 12 human malignant glioma cell lines at clinically relevant concentrations around 1 μM. Gemcitabine is thus approximately 100-fold more active than the congener drug, cytarabine. Gemcitabine cytotoxicity of glioma cells does not require wild-type p53 activity: (i) there was no difference in the susceptibility to gemcitabine between cell lines with wild-type p53 and cell lines with mutant or deleted p53; (ii) ectopic expression of a temperature-sensitive p53 protein either at wild-type (32.5°C) or at mutant (38.5°C) conformation had no significant influence on gemcitabine-induced cell death. Gemcitabine cytotoxicity was unaffected by the antioxidants, N-acetylcysteine and phenyl- N- tert-butyl-α-phenylnitrone. There was no correlation between the susceptibility to gemcitabine and the endogenous expression of the B cell lymphoma-2 (BCL-2)-family proteins BCL-2, BCL-XL, myeloid cell leukemia-1 (MCL-1), BCL-2-associated X protein (BAX), BCL-2 homologous antagonist/killer (BAK) and BCL-XS. Ectopic expression of BCL-2 moderately attenuated gemcitabine-induced cell death. Similarly, preexposure to the synthetic steroid, dexamethasone, which is commonly used to control cerebral edema in brain tumor patients, reduced gemcitabine cytotoxicity. We conclude that the clinical evaluation of gemcitabine for the adjuvant chemotherapy of malignant glioma is warranted.

悪性神経膠腫に対するACNU/VP16併用療法の治療成績 : 第2報 補助化学療法としての臨床的意義について

悪性神経膠腫に対するACNU/VP16併用療法の治療成績 : 第2報 補助化学療法としての臨床的意義について

Assessing response to chemotherapy in malignant glioma: The role of steroids

To the Editor: We agree with Grant et al.1 that it is important to establish the relation between the extent of chemotherapy response and time to tumor progression or survival in patients with malignant glioma. In light of the emerging chemotherapy agents with cytostatic and anti-angiogenic properties, this article is both timely and important to the design of future clinical trials. Although the statistical method used in the analysis is well entrenched in neuro-oncology literature, we offer our opinion on this matter because this is a mistake commonly made by investigators in this field. Because …

Assessing response to chemotherapy in malignant glioma: The role of steroids

Assessing response to chemotherapy in malignant glioma: The role of steroids

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Hypericin-induced apoptosis of human malignant glioma cells is light-dependent, independent of bcl-2 expression, and does not require wild-type p53

Hypericin and tamoxifen are experimental agents for the adjuvant chemotherapy of malignant glioma. We report that hypericin and tamoxifen induce apoptosis of 7 human malignant glioma cell lines in a concentration- and time-dependent manner. Illumination is essential for the cytotoxicity of hypericin but not tamoxifen. Apoptosis is unaffected -by inhibitors of RNA and protein synthesis or free radical scavengers, does not require wild-type pS3 activity, and occurs in glioma cells expressing high levels of bcl-2. There is no correlation between hypericin and tamoxifen-induced cytotoxicity and inhibition of protein kinase C (PKC). Ectopic expression of a murine bcl-2 transgene provides modest protection from tamoxifen but does not affect hypericin toxicity. Hypericin and tamoxifen do not modufate glioma cell killing induced by tumor necrosis factor-α (TNF-α) or CD95 ligand. Both drugs augment the acute cytotoxicity of various cancer chemotherapy drugs but fail to shift their EC50 values in modified colony formation assays. These data do not provide further supportive evidence how to enhance the limited efficacy of tamoxifen treatment for human malignant glioma. However, hypericin is a promising agent for the treatment of malignant glioma if local photodynamic activation of hypericin in the glioma tissue can be achieved. [Neural Res 1997; 19: 459-470]

O-1-1 - Tailored chemotherapy of malignant gliomas

O-1-1 - Tailored chemotherapy of malignant gliomas

Chemotherapy response criteria in malignant glioma.

No one has ever proven a relationship between the extent of response to chemotherapy in malignant glioma and time to progression or survival. We studied the predictive value of "imaging response" following two courses of nitrosourea-based chemotherapy in 136 patients with recurrent astrocytoma/malignant glioma. We performed image analysis by blinded side-to-side comparison of sequential studies, and categorized response into: partial response (PR) (>50% reduction), minor response (MR) (25-50% reduction), stable disease (SD) (<25% change), progressive disease (PD) (>25% increase). Patients with PR, MR, and SD did not differ with respect to time to progression (TTP) (p > 0.2) or survival (p > 0.2). Median TTP was 27 weeks for SD, 43 weeks for MR, and 30 weeks for PR. Patients with PD had a significantly reduced survival (p < 0.001). Median survival was 21 weeks for PD, 53 weeks for SD, 63 weeks for MR, and 48 weeks for PR. The lack of relationship between response and TTP may be due to early relapses in patients with response, a cytostatic benefit of chemotherapy in some patients who do not have an objective response, or a relatively favorable natural history in some tumors that do not respond to chemotherapy. Our data do not support the validity of current response grading, assessed after two courses of chemotherapy. Further research and validation of response criteria is necessary.

Polymeric controlled-release amsacrine chemotherapy in an experimental glioma model.

The purpose of this study was to fabricate and investigate amsacrine containing polymeric rods for use in interstitial chemotherapy of malignant glioma. Ethylene vinyl acetate copolymer (EVAc) rods containing 40% amsacrine (AMSA) were fabricated successfully with an extrusion method. In vitro kinetic studies revealed a high level of reproducibility of the production process. The release of AMSA showed a biphasic pattern consistent with a matrix-type controlled-release system with an initial more rapid release rate followed by a slower and more linear release phase. Release of AMSA was observed for over 6 months and the rods continue to release in a stable fashion. In vitro studies using rat glioma (RG2) in cell culture showed that cells treated with AMSA released from the rods were killed in a dose dependent manner indicating that AMSA incorporated into the polymer remained biologically active. In vivo studies of rats with single AMSA rods implanted five days after RG2 tumour implantation revealed histological evidence of an anti-tumour effect as well as an increased survival (p < 0.0003). The mean survival of the amsacrine treated rats was 78 days with 50% still remaining alive > 5 months after implantation. All control animals developed tumours and died within 15-19 days after tumour implantation (mean = 17 days). Amsacrine implanted animals showed no significant histological or clinical evidence of toxicity. We conclude that amsacrine containing EVAc rods can be safely and efficaciously use against the RG2 experimental glioma in a rat model and warrant further investigation.

Association ofp53 gene mutation with decreased chemosensitivity in human malignant gliomas

Loss of p53 function is involved in tumorigenesis of various human cancers, but the relation between mutation of the p53 tumor-suppressor gene and the chemo- and radiosensitivity of tumors remains unclear. Mutated p53 gene in malignant glioma is often associated with progression and recurrence of malignancy, and these events are closely linked with increased resistance to both chemotherapy and radiation. We have examined the status of the p53 gene in malignant gliomas obtained from 34 patients (glioblastoma: 29 cases, anaplastic astrocytomas: 5 cases). The chemosensitivities of these specimens using 28 kinds of anti-cancer agents were determined using an in vitro assay system. Overall, 12 mutated cases of p53 gene were found in malignant glioma samples. The mean numbers of effective agents were 0.58 for the tumor samples with p53 mutations and 5.00 for tumors without mutations. Our data indicate that p53 gene mutation predisposes to decreased cell killing via chemotherapy in malignant gliomas.

Pre-radiation chemotherapy for malignant glioma in adults.

To review our experience with pre-radiation chemotherapy for malignant glioma. Consecutive adults with newly diagnosed glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma and anaplastic mixed glioma with a Karnofsky Performance Score of 60 or greater were treated with one cycle of procarbazine, lomustine and vincristine or lomustine alone, prior to radiation. Computed tomographic scans were obtained soon after surgery, eight weeks later, after radiation, and at regular intervals thereafter. The effects of chemotherapy and subsequent radiation and durations of tumor control and survival were assessed in this single arm, single center, prospective trial. Thirty-seven patients started chemotherapy, 36 were rescanned eight weeks after diagnosis. Five patients (16%) responded to the first cycle of chemotherapy, three had glioblastoma and two anaplastic oligodendroglioma. Seven (19%) progressed during the first cycle, 6 had glioblastoma; with the addition of radiation one progressive case responded, three stabilized, and three continued to progress. Median times to progression and median durations of survival were 26 weeks and 60 weeks for the entire group, 24 weeks and 44 weeks for glioblastoma, and greater than 104 weeks for anaplastic astrocytoma. Most patients with glioblastoma do not respond to one cycle of nitrosourea-based chemotherapy given prior to radiation, but patients with anaplastic oligodendroglioma sometimes do. Patients with anaplastic astrocytoma may not respond to one cycle of chemotherapy, but often respond to subsequent radiation. Judging by survival results, radiation can be delayed eight weeks without appearing to compromise patient outcome. Pre-radiation chemotherapy with newer agents can be evaluated more fully in the future knowing that brief delays in radiation are unlikely to yield substantially inferior results.

Local chemotherapy with slowly-releasing anticancer drug-polymers for malignant brain tumors

Malignant brain tumors are resistant to many treatments.This report presents the methodology and results of a clinical trial of local chemotherapy of malignant glioma based on slowly releasing anticancer drug-polymers made by our groups. These slowly releasing drug polymer composites were prepared by combining and mutually dispersing anticancer agents with classified monomers containing 10% polymetacrylic methyl acid; this compound was then frozen at − 70°C and exposed to 1 × 10 6 Rad cobalt 60 γ-rays. Thus we prepared a compound of polymers and anticancer agents (mitomycin, adriamycin, 5-Fu and ACNU). We administered locally to the malignant glioma with these polymers. The following techniques were employed for implanting these polymers: (1) implantation into the remaining tumor wall at the resection; (2) implantation into the tumor by the CT-guided stereotactic method. The polymers were implanted into tumors (120 cases) using a combination of radiotherapy and systemic chemotherapy.

Reversal of chemoresistance in malignant gliomas by calcium antagonists: correlation with the expression of multidrug-resistant p-glycoprotein.

Resistance to multiple drugs is often observed in malignant gliomas. The authors used a microtiter tetrazolium test to analyze primary in vitro chemoresistance and chemosensitivity of 15 early cultures of human malignant glioma exposed to 50 micrograms/ml (1,4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU), 50 micrograms/ml cisplatin, 1 microgram/ml vincristine, or combinations of these chemotherapeutic agents. Primary chemoresistance was observed in 87% of tumors for ACNU, in 87% for cisplatin, and in 83% for vincristine. All tumors were examined for expression of multidrug-resistant p-glycoprotein, a transport protein of 170,000 D, by means of immunohistochemical staining with the JSB-1 antibody on paraffinized tumor sections. Eight of 15 specimens (53%) showed positive staining for the monoclonal antibody. Primary chemoresistance was overcome by addition of the calcium antagonists verapamil or nimodipine to the cultures if the original tumor expressed p-glycoprotein (p < 0.01 for verapamil, p < 0.05 for nimodipine). In tumors not expressing p-glycoprotein, addition of calcium antagonists to the cell cultures did not influence primary chemoresistance. It is concluded from these data that addition of calcium antagonists to the adjuvant chemotherapy of malignant gliomas might overcome primary chemoresistance in tumors expressing the multidrug-resistant phenotype.

Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults

Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults

Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults

The value of chemotherapy after standard postoperative external beam radiation in the treatment of malignant gliomas remains controversial. Despite recent recommendations from the Brain Tumor Cooperative Group that chemotherapy should be considered part of the standard treatment of patients with high-grade astrocytomas, several recent trials have questioned the efficacy of this approach. Using results from 16 randomized clinical trials involving more than 3000 patients, the authors compared the survival rates of patients who received radiation alone or radiation with chemotherapy. The combined data were analyzed using the statistical method of meta-analysis as described by DerSimonian and Laird. The estimated increase in survival for patients treated with combination radiation and chemotherapy was 10.1% at 1 year (95% confidence interval, 6.8, 13.3%) and 8.6% at 2 years (5.2, 12.0%). These absolute increases in survival (treated-control [TC]) in patients treated with chemotherapy represent relative increases (T-C)/C of 23.4% at 1 year (15.8, 30.9%) and 52.4% at 2 years (31.7, 73.2%). This survival advantage is conferred by several different chemotherapeutic agents. When the prognostic variables of age and histology are factored into the analysis, however, the data suggest that the survival benefit from chemotherapy occurs earlier in patients with anaplastic astrocytoma (AA) than in patients with glioblastoma. The authors concluded that chemotherapy is advantageous for patients with malignant gliomas and should be considered part of the standard therapeutic regimen. Additional randomized trials using optimal radiation and chemotherapy may still be needed to precisely define which subgroups of patients, based on prognostic variables, will benefit most from chemotherapy after radiation.

Effect of intra-arterial cisplatin and 1,3-bis(2chloroethyl)-1-nitrosourea (BCNU) dosage on radiographic response and regional toxicity in malignant glioma patients: proposal of a new method of intra-arterial dosage calculation.

The frequency of both neurologic toxicity and therapeutic response due to intra-arterial (IA) chemotherapy is decreased by dose reduction. A method to individualize IA drug dosage is needed to provide each patient with the safest, most effective dose. Most trials of IA chemotherapy for malignant glioma have used body surface area (BSA) to calculate dosage; but brain size and arterial distribution do not correlate well with BSA. Fixed doses of cisplatin and BCNU were used in combination to perform 35 IA infusions in 20 malignant gliomas patients. Doses modified by the number of major intracranial vessels supplied by the infused artery were used in 34 infusions in 19 patients. Patients receiving 150 to 200 mg CP and 300 mg BCNU had an incidence of neurologic deficit of 5.6% if greater than or equal to 3 vessels were supplied by the infused artery compared to 42% for those with only 2 vessels. This crude dose modification maintained efficacy while reducing neurologic toxicity. Further refinement is possible using well established intra-arterial pharmacokinetic principles. Intra-arterial dosing based on volume flow at the site of infusion would yield a more reproducible exposure of the infused capillary bed to a drug than methods currently in use. More consistent drug exposure should reduce toxicity due to over dosing and treatment failure due to under dosing.

Treatment of malignant brain tumor with slowly releasing anticancer drug-polymer composites

This report presents the methodology and results of a clinical trial of local chemotherapy of malignant glioma based on slowly releasing anticancer drug composites. The small cylinders of the composites were prepared by radiation-induced copolymerization of diethylene glycol dimethacrylate with polyethylene glycol #600 dimethacrylate in the presence of anticancer drugs such as adriamycin, 5-fluorouracil (5-Fu), and nimustine hydrochloride (ACNU) at −78°C, using γ-rays from a 60Co source. The composites obtained were administered locally to the malignant glioma. The following techniques were employed for the implantation of the specimens: 1. (1) Implantation into the remaining tumor wall at the resection. 2. (2) Implantation into the tumor by the CT-guided stereotactic method. We have implanted them into the tumors of 100 cases by a combination of radiotherapy and systemic chemotherapy.

Intravascular streaming during carotid artery infusions

Intra-arterial carotid artery chemotherapy for malignant gliomas is limited by focal injuries to the eye and brain which may be caused by poor mixing of the drug with blood at the infusion site. This inadequate mixing can be eliminated in animal models with diastole-phased pulsatile infusion (DPPI) which creates 1-ml/sec spurts during the slow blood flow phase of diastole. Before treatment with intracarotid cisplatin, 10 patients with malignant gliomas were studied to determine whether intravascular streaming occurs after intracarotid infusion in humans, and if so, if it is reduced with DPPI. Regional cerebral blood flow (rCBF) studies were performed by intravenous injection of H2(15)O and positron emission tomography. This was followed by supra- or infraophthalmic internal carotid artery (ICA) injections of H2(15)O with either continuous infusion or DPPI. Local H2(15)O concentration in the brain was determined and the images of radiotracer distribution in the continuous infusion and DPPI studies were compared to the rCBF images. Intravascular streaming of the infusate was identified by a heterogeneous distribution of the infused H2(15)O in brain compared to rCBF. Extensive and variable intravascular streaming occurred in three patients who received infusions into the supraophthalmic segment of the ICA. Some brain areas received up to 11 times the expected radiotracer delivery, while other regions received as little as one-tenth. This streaming pattern was markedly reduced or eliminated by DPPI. In the five patients who received infraophthalmic infusions, a minimally heterogeneous distribution of the infusate was detected. The authors conclude that extensive intravascular streaming accompanies supraophthalmic ICA infusions in patients. The magnitude of streaming can be substantially reduced or eliminated with DPPI. Those who perform intra-arterial infusion should consider using DPPI to assure uniform drug delivery to brain.