Clinical Trial Summary
Voltage Gated Sodium Channels Over the years, there is more evidence that ionic channels are
involved in the oncogenic process. Among these, voltage gated sodium channels (VGSC)
expressed in non-nervous or non-muscular organs are often associated with the metastatic
behavior of different cancers.
Expression of VGSCs has been reported both in vitro and/or in vivo in a range of human
carcinomas, including breast cancer Ion channels are major signaling molecules expressed in a
wide variety of tissues. They are involved in determining a variety of cellular functions
like proliferation, solute transport, volume control, enzyme activity, secretion, invasion,
gene-expression, excitation-contraction coupling, and intercellular communication.4 VGSC
activity contributes to much cellular behavior integral to metastasis, including cellular
process extension, lateral motility and galvanotaxis, transverse invasion, and secretory
membrane activity.
A correlation between Na transport and oncogenesis has been widely reported in literature. In
1980, transformed mouse mammary cells were shown to have 3-fold higher intra-cellular sodium
content than untransformed cells.5 Additionally evidence suggest that increasing the inward
sodium current through voltage gated sodium channels increased the invasive capacity of
breast cancer.6 Also, growth and proliferation of mammary adenocarcinoma cells can be
inhibited by Amiloride suggesting that epithelial Na channels (ENaC) activity is correlated
with proliferation of breast cancer cells
Current evidence suggests that VGSC activity is necessary and sufficient for cancer cell
invasiveness8. A recent in vitro study has shown that the human MDA MB 231 breast cancer cell
line expressed functional VGSCs9. However, the molecular nature of the VGSC and its
functional relevance to breast cancer in vivo are currently under study.
Surgical operations for cancer have been reported to induce dissemination of cancer cells
into surrounding tissues or into the circulation10,11and infiltration anesthetics can inhibit
immune response12-14. Although the mechanism remains to be elucidated, infiltration
anesthetics such as lidocaine have membrane- stabilizing action (Seeman, 1972) and these
agents could have direct effects on cancer cells. Therefore, it is important to clarify the
effects of infiltration anesthetics on behavior of the tumor cells.
Commonly used local anesthetic agents inhibit the VGSCs and also possess a unique membrane
stabilizing action through other unknown mechanisms. A study by Mammota et al 15 reported
that lignocaine, effectively inhibited the invasive ability of human cancer (HT1080, HOS, and
RPMI-7951) cells at concentrations used in surgical operations (5-20 mM). Lidocaine reduced
the invasion ability of these cells by partly inhibiting the shedding of HB-EGF from the cell
surface and modulation of intracellular Ca2+ concentration contributed to this action. In
addition, lidocaine (5-30 mM) infiltrated around the inoculation site, inhibited pulmonary
metastases of murine osteosarcoma (LM 8) cells in vivo.
Dose of lidocaine15:
40 mM (1%) lidocaine is usually used for infiltration anesthesia for surgical operations.
Lower concentrations (1-20mM) of lidocaine were sufficient to suppress the invasive ability
of cancer cells14. One mM lidocaine inhibited the invasive ability of HT1080 cells by about
50%, and 20 mM lidocaine inhibited the invasion ability completely. Lidocaine also inhibited
dose-dependently the invasive ability of HOS and RPMI-7951 cells, although it was less
effective on HOS cells. Lignocaine exerts its anesthetic action by obstructing the sodium
channel 16 however, 10 mMof tetrodotoxin (TTX), a specific sodium channel inhibitor, had
little effect on the invasive ability of HT1080 cells. Ten mM lidocaine-N-ethylbromide (NEB),
which does not cross the cell membrane, also had little effect on the invasive ability of the
cells.
Objectives
Primary Objective:
• To assess the in-vivo ability of local anesthetics agents like lignocaine to decrease the
dissemination of cancer cells during surgery and improve the disease free interval
Secondary Objective
• To assess the in-vivo ability of local anesthetics agents like lignocaine on impacting long
term survival.
Methodology / Treatment plan
The study drug (0.5% lidocaine 60mM) will be tested in the intraoperative setting prior to
surgery will be tested in a randomized setting.:
Arm A: 60mM of 0.5% lignocaine will be injected peritumoral prior to excision. The local
anesthetic should be injected on all 6 surfaces of the tumor and also within the tumor. Wait
for 7 minutes for its action followed by surgery. (Intervention arm) Arm B: No injection of
lignocaine prior to excision (Control arm)
