Use of Elemene in Treating Intracranial Malignant Tumors
XU Yinghui1, DONG Bin1, HOU Jusheng 2, LUO Qizhong1 (1 Neurosurgery
Department of Ren Ji Hospital, Shanghai Second Medical University, Shanghai
200001, 2 Neurosurgery Department of the Second Affiliated Hospital of Dalian
Medical University, Dalian, Liaoning 116023)
Key words: elemene; intracranial malignant tumor
Ezhu
extract - elemene is a new second category non-toxic anti-tumor drug developed
by Chinese medical workers after nearly 20 years’ studies. Pharmacological
experiments confirmed that elemene had strong suppression and destruction
effects on a variety of tumor cells in vitro and in vivo [1]; in 1990s, Hou
Jusheng et al [2] for the first time used elemene for intracranial cancer
treatment and achieved encouraging results. Therefore, a large number of
experiments and clinical studies found that elemene had exact inhibiting effect
on a variety of tumors and showed broad-spectrum anti-tumor characteristics.
Elemene not only had direct anti-tumor effect, but offered immune protection; it
had few side effects, caused no significant harm of liver and kidney and no
bone marrow suppression. Because of its low toxicity, high efficiency and the
advantages of broad-spectrum, elemene attracts increasing attention from
medical practitioners. But its mechanism and efficacy in treating intracranial
malignant tumors still need further study.
I.
Pharmacological Research
1. Chemical components: elemene is an oily compound separated from Ezhu
volatile oil. Ezhu is a curcuma plant that grows in
2. Pharmacokinetics: the in-plasma drug concentration-time curve after
intravenous injection was a two-mode type: t1 / 2 α = 11. 2 min, t1 / 2 β =
10.5 h; drug concentration in the lung, spleen, liver and lymph tissue was the
high with the highest in the lung; the drug could pass through the blood -
brain barrier and reach brain tissues. The average plasma protein binding rate
was 97.7%. As elemene is a volatile oil, it is mainly discharged through the respiratory
tract. Long-term toxicity tests found that the drug d had no significant impact
on the blood, liver and kidney function of dogs and rats [4].
II.
Research on the anti-tumor mechanism of elemene
1. In-vitro study on elemene’s inhibition of the proliferation of glioma cells:
Modified
methyl thiazolyl tetrazolium (MTT), 3H-thymidine deoxy riboside (3H-TdR)
and colony-forming experiments were used to examine the function of elemene on
glioma C6 and SHG-44 cell lines. The study found the inhibition of
proliferation of gliomas increased with the dose. Under the same concentration,
the inhibition effect increased with the time. The inhibitory concentration 50%
(IC50) was examined with different time duration of elemene treatment (1 ~ 4 d).
It was found that the concentration of C6 Cells was 7.33~11.02 mg / L, that for
SHG-44 cells was 13.29~27.16 mg / L, indicating under the same drug
concentration, C6 cells were more sensitive than SHG-44 cells [5].
Elemene
induced apoptosis of glioma cells: apoptosis is a programmed cell death process
controlled by a variety of genes, which is now considered the main mechanism of
anti-tumor drugs. Zhou Hongyu [5] used Hoechst 33258
propidium iodide (PI) staining to observe the morphological changes of apoptosis
cells and found after using elemene, the nuclear coloring of glioma cells densified, the chromosome condensed and moved
closer to the nuclear membrane, DNA fractured and apoptosis bodies appeared. In
comparison, the nuclear DNA of normal cells was scattered, the staining of the
nucleus was light and equal. FCM analysis showed that, when C6 / SHG-44 cell
lines were not dealt with, their natural apoptosis rate was low, and the application
of different concentrations of elemene could induce apoptosis. DNA content figure
showed before G0 / G1 peak, there was an apparent peak of apoptosis, indicating
featured change compared with the control group. After using elemene, C6 cell
DNA gel electrophoresis showed obvious ladders, while ladders did appear in the
control group. Morphological observation, DNA biochemical change and flow
cytometry analysis all proved that elemene could induce apoptosis of gliomas.
It is worth noting that the experiment observed that the apoptosis inducement
effect appeared 3 days after using elemene, and intensified 5 days after the
use.
Elemene induced
differentiation of glioma cells: Differentiation inducing has attracted growing
concern as a new area of tumor biological therapy. Differentiation inducing
refers to the phenomenon that malignant cancer cells differentiate to normal
cells using in vitro and in vivo inducements. Studies found that when
low-concentration elemene was used to deal with glioma C6 / SHG-44 cell lines, the
glioma cells showed morphological change to mature cells; the expression of Ki-67
lowered; while the expression of glial fibrillary acidic protein (GFAP) increased,
suggesting that elemene can reverse the malignant phenotype of glioma cells
[5].
2. In-vivo study:
elemene could inhibit tumor suppression and enhance immunity of tumor-loaded
animals. Zhou Hongyu [5] planted the heterogeneous type of human glioma SHG-44 cells
model in the forelimb armpit of nude mice and found in the group treated with 40
μg/ml elemene, it took longer time for the tumor to develop than the control
group; in the group treated with 60 μg/ml elemene, tumor cells in the 3 mice
did not grow (P <0. 01). In tumor inhibition tests, when elemene 150 mg/kg was
injected into the abdominal cavity and local body of mice, tumor growth rate
slowed down significantly. The study of mouse brain nerve G422 gliomas found
[6]: elemene could directly kill the G422 tumor cells by inducing necrosis and
increase the level of IL-2 (interleukin-2) level and tumor necrosis factor (TNF)
and strengthen the immunity of T cells to achieve anti-tumor effect.
Huang Qiang, etc. [7] applied elemene and dual-specific antibody to jointly
deal with severe combined immuo deficient (SCID) mice, and found it took more
time for the treated group to develop tumor, suggesting that elemene and double
special antibody showed synergy in treating cancers.
III. Drug use and its
side effects
Experiments were done on dogs and found when injected with elemene 150 mg/kg into
the artery and vein of the animals, they did not show epilepsy, liver and
kidney dysfunction, bone marrow suppression and abnormal electrocardiogram; when
elemene 80μg/ml was locally used in the rat brain tissues, there was no obvious
organic damage except local congestion and leukocyte infiltration. But when
elemene was injected into the ventricle and arachnoid, some animals showed irritability,
seizures and other adverse reactions.
IV.
Clinical research
In early 1990s, Hou Jusheng et al. [2] first used elemene to treat intracranial
malignant tumors, including glioma, metastatic carcinoma and malignant
meningeal
tumors and myeloma, and studied drug administration, security doses, side
effects, achieving encouraging results. Clinical studies found elemene had
exact efficacy on a variety of tumors and also could increase the immune
function, and showed synergy with radiotherapy and chemotherapy. Elemene could
pass through the blood-brain barrier, compared to most cytotoxic chemotherapy
drugs, it caused low drug toxicity, no significant liver and kidney damage and
no bone marrow suppression. This is undoubtedly an important new way of
treatment for malignant intracranial cancers.
Tan Pingguo [8] used
continuous infusion of elemene on 23 patients suffering from malignant brain
tumor, of whom 13 patients had with malignant glioma, 10 had brain metastases.
Elemene of 400 to 800 mg/d was percutaneously catheterized into the internal
carotid artery, or percutaneously catheterized into the subclavian vein or
elbow median static vein with continuous infusion by a pump. Results: after
treatment the average tumor size reduced by 62.2 percent; three patients
completely relieved, 14 patients partially relieved; the average survival time
of the treatment group was
Li Qingfang [9] used elemene in the carotid artery by pressurized drip
treatment in 30 patients with brain tumors. The efficient rate was 73.3
percent. Treatment found no side effects.
Chen Baozhi [10] reported
11 cases of treating malignant brain tumor via internal carotid artery infusion
of elemene, including 2 glioma patients and 9 patients with metastatic
carcinoma. CT found after treatment the tumor in 2 patients completely
disappeared, in 5 patients, the size of tumors shrank by more than 50 percent,
in 3 patients, the size of tumors shrank by less than 50 percent, and in 1
patient, the size increased. The Remission rate was 63.6 percent. All patients
did not show serious adverse reactions.
Xu Hongsheng, etc. [11] found in elemene treatment group, the activity of
plasma Super oxide dismutase (SOD) was significantly higher than the control
group, and the group treated with
Wang Huaijin, etc.
[12] treated 38 patients with metastatic brain cancer with elemene, 39.5% of
them completely (2 patients) or partially relieved. The T cell subgroups: T3
(T3-lymphocytes, representing mature T-lymphocytes), T4 (T4-lymphocytes, representing
helper T lymphocytes), T4 / T8 (T8-lymphocytes, killer T-lymphocyte,), IL-2
levels, TNF-α content and lymphocyte transformation rate (LTR) had all increased,
T8 declined. KPS assessment showed higher scores of 21 cases and lower scores
of 4 cases. Exception phlebitis and local injection site pain, no other side
effects were reported. It shows the good prospect of elemene in treating
cancers.
Hou Jusheng, etc.
[13] used multiple injection of elemene on 19 patients with brain tumors, which
had achieved good effect and provided valuable experiences for local application
of elemene.
In addition, elemene worker in treating head and neck cancer, lung cancer,
liver cancer, advanced gastric cancer, colorectal cancer, bladder cancer,
leukemia and malignant effusion of the chest and abdominal cavity. Moreover,
when used together with other chemotherapy drugs, elemene could improve and
prevent bone marrow suppression caused by other chemotherapy drugs. [14] Elemene
could improve the sensitivity to chemotherapy drugs, or even reverse drug
resistance of late-stage patients. [15]
V. Problems and
Prospects
Studies found: ① For some intracranial malignant tumors, elemene can treat them
effectively; for some others, it did not work. It is still difficult to
determine whether it is more effective in treating glioma or in treating metastatic
carcinoma. ② Gliomas had complicated classification and a number of pathological
subtypes. The sensitivity to different types of gliomas needs to be further
explored. The standardized administration of elemene also needs to be verified
by clinical research centers. The anti-tumor mechanisms and related basic
research need go further, which is now a major obstacle. As an effective
extraction of natural herbal medicine, elemene has advantages that chemical
synthetic drugs do not have. Its anti-tumor and immunoregulation role will have
a more far-reaching application in preventing recurrence of malignant
intracranial tumors, but there is still no such research in this area.
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