Lung cancer is still one of the major health problems. Deaths from lung cancer still dominate among all malignancy. Nearly 10 million patients are reported dead in 2018.
Cancer treatment and prevention has changed quite a lot compared to previous years. Therapy based on the effectiveness of the natural immune system (immunotherapy), the use of particular chemotherapy drugs that work on specific targets (targeted therapy), and various other modalities including hormones and laser are used to kill cancer cells.
Nevertheless, the results obtained are not yet fully encouraging. Cancer cell resistance to chemotherapy drugs and drug side effects are one of the obstacles.
Conventional chemotherapy is still an option in the guidelines or guidelines for the management of lung cancer, especially the type of nonsmall cell lung cancer (NSCLC). The combination of gemcitabine (GEM) and paclitaxel (PTX) are two types of cytotoxins that can still be given to patients with advanced-stage lung cancer.
Different ways how the drugs work, GEM as an inhibitor of DNA synthesis and PTX functions to deactivate the tubular system of cells; became the focus of researchers to use in eliminating cancer cells. The following research also wants to see the potential combination of these two drugs as an alternative therapy. The study was conducted in vitro using cancer cells types A549 and H520 and used mice as a mouse tumor model. The order of administration and dosage of the drug is a paramount concern.
Synergistic Effects through Acetylation and Tubulin Polymerization
The combination of two or more three drugs is not new in medicine. Management breakthrough by combining several drugs in the field of infectious diseases and malignancies has been going on for a long time. Besides a combination of chemotherapy drugs, the use of antiviral medications for HIV / AIDS is felt to be very helpful in reducing mortality.
Discussion of drug combinations will always be related to the three effects: synergism, additives, and antagonism. Synergism or a synergistic effect is different from just an additive effect (additive) and even contrary to the antagonism effect (antagonism). Synergy means getting the maximum benefit from the efficacy of each drug. It means that each drug in combination has the potential to increase the action of other drugs.
Meanwhile, additives occur when you only get the benefit of one of the drugs used. Understanding synergism and additives are not as easy as simple algebra. For example, A + B> B or A + B> A. There are calculations such that synergism, additives and antagonism will be obtained.
In this study, based on each effective concentration of 50 percent (IC 50 ), it was found that the use of GEM before PTX (GEMàPTX) was better than PTX before GEM (PTX àGEM) and GEM PTX simultaneously (GEM + PTX). The synergistic effect of GEMàPTX is obtained from the use of small doses of each drug that is still effective. The effectiveness of this dose is proven by the low growth of cancer cells in vitro.
To explain the synergism of a drug combination, it did not require a specific mechanism or method of action. However, to corroborate the scientific reasons for this finding, we proceeded with several examinations.
PTX effects on tubules are the target of further experiments. The scanning of protein acetylated tubulin and polymerized tubulin levels are carried out through Westernblot (WB) and immunofluorescence. From the WB, it was found that the acetylated tubulin protein in the higher GEMàPTX group was characterized by a large band. Likewise, tubulin polymerization marked by the formation of microtubule bundle was seen by immunofluorescence painting.
Synergism assessment is also done through apoptosis (dead cell) and scratch (cell movement assessment) tests. Cancer cells in the GEMàPTX group appear to have more apoptosis and are slower to move.
To further emphasize the synergistic effect of drug combinations, an in vivo study was conducted. Experimental mice were injected with cancer cells via subcutaneous injection to cause tumors and then given chemotherapy drugs, both in combination and single treatment. The tumor growth chart was assessed for one month. The final results showed that the group given GEM before NabPTX (the newest form of PTX) had lower tumor mass growth.
Combination of GEM à PTX for Advanced Lung Cancer Therapy
The results of in vitro and in vivo research illustrated that the success of the PTX GEM combination is strongly influenced by order of drug administration. In contrast to previous studies, we have shown that small doses of GEMàPTX can produce synergistic effects. This synergism can be seen from a series of tests conducted.
We assume that synergism occurs because of the strengthening effect of PTX by GEM in the process of acetylation and tubulin polymerization. Furthermore, small doses of GEM still function optimally in inhibiting DNA synthesis. We hope that these results can inspire further research and become a breakthrough in the management of advanced lung cancer.
Author: Wiwin Is Effendi, dr., SpP.
More detailed information and discussion can be seen in our publications by accessing
Effendi WI, Nagano T, Tachihara M, Umezawa K, Kiriu T, Dokuni R, Katsurada M, Yamamoto M, Kobayashi K, Nishimura Y