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INTRODUCTION
Anticancer
chemotherapy is one of the standard ways of treatment of oncologic patients.
Despite the extraordinary high cost of development and study of new anticancer
chemotherapy drugs, the synthesis of new chemical antitumor substances
continues. Unfortunately, chemotherapy has many side effects, cytostatic and
cytotoxic effects on non-tumor cells of living organisms are the main ones.
Paradoxically, relatively few topical scientific articles are devoted to this
clearly negative property of chemotherapy drugs with respect to non-tumor
cells. The search for “cancer chemotherapy side effect minimization” revealed
only 5 articles within PubMed on August 20, 2019. This can be possibly
explained by the fact that the side effect of cytostatics is not difficult to
assume, given the multifactorial mechanisms of their action at the level of
DNA, RNA, enzymes, mitochondria, ribosomes, microtubules, spindle, cell
membrane, etc. The negative mechanisms of chemotherapy primarily affect the
energy activity of living cells, a variety of enzymatic pathways, protein
synthesis, mitochondria activity, DNA replication mechanisms, cell division and
other natural mechanisms that are the basis of normal life of any living cells.
The ideal way out of this situation is to create new chemotherapeutic drugs with
no or minimal side effects in relation to non-tumor cells. Pharmaceutical
companies are working in this direction, but, as you know, this process is
extremely expensive and still has not ended with the creation of a new
chemotherapy without side effects. Therefore, it is advisable to look for new
methodological solutions to the problem.
There is
another intriguing question in solving this problem. Existing recommendations
for preclinical and clinical studies include in vitro experiments (monolayer of cells, i.e., 2D construction)
and 3D observations, that is, in vivo
experiments in acute or chronic observations. It is important that the
pronounced antitumor effect in vitro
manifests itself in vivo differently
often during testing of new drugs and is sometimes replaced by the opposite
proliferative effect. And even more difficult problem lies in a wide variety of
individual patient sensitivity.
The authors
decided to focus on the problem of minimization of side effects when
chemotherapy is combined with nanoparticles, which are traditionally used for
diagnostic purposes, both in experimental and clinical settings. Some
researchers are trying to find a kind of replacement for existing drugs,
developing combinations of nanoparticles in order to achieve a pronounced
antitumor effect [1-3]. For example, the use of
nanoparticles in the treatment of melanoma allows increasing stability of
standard antitumor drugs, improve permeability of epithelium for
chemotherapeutic agents and carry out a peculiar “targeting” of chemotherapy
drugs to melanoma cells [1]. Such tactics of new antitumor drugs use is
extremely expensive and, unfortunately, still not effective enough. A range of
researchers try using nanoparticles as a kind of carriers of chemotherapeutic
agents, which allows increasing targeted action of chemotherapeutic agents and
reducing their side effects. It was found that induction chemotherapy in combination
with chemoradiotherapy significantly improves patients’ survival compared to
chemoradiotherapy alone in nasopharyngeal carcinoma [4].
In fact, there
are solutions that affect the interests of both patients in terms of antitumor
efficacy and developers of new drugs. Previous studies at the Brain Center (the
Institute of Physiology of the National Academy of Sciences of Belarus) showed
that the antitumor activity of classical anti-
There is a
rational way out of this situation: the method of using a classical
chemotherapy in combination with nanoparticles to increase the effectiveness of
a combination of substances, which will reduce the dose of a chemotherapeutic
drug, but maintain its antitumor effect. Since all chemotherapy drugs have
pronounced toxic action (side effects), a reduction in the dosage of
chemotherapy drug is the basis for reducing side effects. In vivo and in vitro
experiments were performed in previous studies in the first stages of new
technique screening in order to identify those dosages of nanoparticles at
which their antitumor results are not manifested. Thus,
a new step has been taken to reduce the toxicity of nanoparticles in future
drug combinations. In addition, selection from a variety of chemotherapeutic
drugs was based on their combination with nanoparticles, which were used in
indifferent doses, but in combination with cytostatics allowed achieving
antitumor effects in vivo and in vitro with reduction in dosage of
chemotherapeutic agents by 10, 100 and even 1000 times [5-8]. In vitro experiments demonstrated
antitumor activity of nanoparticles with several chemotherapeutic agents
(Cisplatin, Carboplatin, Etoposide, Cytarabine, Methotrexate, Gemcitabine) in
relation to C6 glioma [5] and cells of primary brain tumors from the
intraoperative material of the Republican Scientific and Practical Centre of
Neurosurgery and Neurology of the Ministry of Health of the Republic of Belarus
[5-7]. In this case, it is inexpedient to distract the attention of specialists
on questions about induction, cytoreductive or another form of chemotherapy,
considered in this article. These issues will be important at the stage of
technology introduction into clinical practice in the design of clinical
protocols.
Antitumor
effects seemed paradoxical in severity when nanoparticles were combined
(dosages were used at which tumor cell death did not develop) with classical
chemotherapeutic agents at the first stages of new technique in vitro testing [5]. But namely a
combination of nanoparticles and chemotherapeutic agents allowed achieving the
death of tumor cells in in vitro
experiments in those ratios that were equivalent to cell death when using
chemotherapeutic drugs in dosages recommended in international community protocols.
So, let us pay attention once again that the paradox of the experiment lied in
the fact that nanoparticles in dosages that do not have toxic antitumor
effects, when combined with chemotherapeutic drugs, can achieve basically total
death of tumor cells. Such effect is desirable for an oncologist, but cannot be
achieved in reality with sole action of chemotherapeutic agents. However,
combination of nanoparticles and chemotherapeutic agents, which allows reducing
the doses of cytostatics by tens and hundreds of times preserves targeted
antitumor efficacy of chemotherapeutic drugs, comparable to that recommended in
international tumor therapy protocols [5-7].
Unfortunately,
the mechanism of such increased antitumor efficacy of the combined action of
nanoparticles and chemotherapeutic agents is still not clear. It is
hypothetically assumed that dendrimers act as peculiar carriers of
chemotherapeutic agents and increase due to their three-dimensional structure
the interaction density of cytostatics with tumor cells. Such phenomenon is one
of the conditions for increase in concentration of antitumor substances in
various parts of tumor tissue. Fullerenes can increase permeability of
chemotherapeutic agents into tumor cells cytosol [5-8]. Therefore, the likelihood
of a more effective antitumor activity of chemotherapy drugs is increased. Such
conclusions are hypothetical at this stage of research and open prospects for
new projects to clarify the mechanisms of antitumor effects.
So, there is an
experimentally identified phenomenon of the ability of nanoparticles in
indifferent doses in combination with chemotherapeutic agents to reduce their
dosages recommended by international protocols by tens of times. The lower is
the dose of chemotherapy drug, the less normal cells and tissues of the whole
organism are damaged, the proliferative potential of endogenous stem cells is
preserved [9] and, thus, the life of patients with fatal oncological process is
prolonged.
There is an
important fact of the so-called rebirth of classical chemotherapy drugs [8-10].
We are talking about reduction of side effects of these substances when
combined with nanoparticles (it is important to use nanoparticles in
indifferent dosages). Such strategy is attractive for pharmacological companies,
since previously developed production technologies will allow increasing the
effectiveness of previously developed chemotherapeutic drugs considering the
new methodology and, thus, increasing the profitability of production [11]. The
oncological process is multifactorial. It is necessary to make maximum use of
synergistic effect of combination therapy to achieve the maximum therapeutic
result in cancer patients [12,13]. Such strategy will make it possible for
positively use the features of therapeutic agents to overcome natural
heterogeneity of tumors in a particular patient, taking into account his
individual characteristics.
CONCLUSION
The problem of
radical therapy for cancer patients has not yet been resolved. The lack of a
clear idea of the mechanisms of carcinogenesis is one of the reasons for this
situation in oncology. The search for new therapies in oncology continues along
with the search for an answer to the question of the origins of uncontrolled
proliferation of tumor cells. The authors draw readers' attention to the
additional resources of chemotherapy that are discovered by combining classical
chemotherapy with nanoparticles. Reduction in dosages of chemotherapy drugs,
which is accompanied by weakening of their toxic side effects while maintaining
high antitumor activity, is one of the positive consequences of such
combinations.
ACKNOWLEDGEMENT
Our research project “Molecular markers and
Raman spectroscopy for evaluation of correlation between cellular heterogeneity
in tumor tissue and primary culture from the tumor tissue” was partially
sponsored by Belarus-Lithuania Fund: 2019-2020 (M19LITG-002).
1.
Chou YP, Lin YK, Chen CH, Fang JY (2017) Recent advances
in polymeric nanosystems for treating cutaneous melanoma and its metastasis.
Curr Pharm Des 23: 5301-5314.
2.
Li J, Chen R, Ji M, Zou SL, Zhu LN (2015) Cisplatin-based
chronotherapy for advanced non-small cell lung cancer patients: A randomized
controlled study and its pharmacokinetics analysis. Cancer Chemother Pharmacol
76: 651-655.
3.
Ang CY, Tan SY, Zhao Y (2014) Recent advances in
biocompatible nanocarriers for delivery of chemotherapeutic cargos towards
cancer therapy. Org Biomol Chem 12: 4776-4806.
4.
Zhang Y, Chen L, Hu GQ, Zhang N, Zhu XD, et al. (2019)
Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma.
NEJM.
5.
Shcharbin D, Dzmitruk V, Shakhbazau A, Goncharova N,
Seviaryn I, et al. (2011) Fourth generation phosphorus-containing dendrimers:
Prospective drug and gene delivery carriers. Pharmaceutics 3: 458-473.
6.
Kulchitsky V, Talabaev MV, Chernov AN, Grigoriev DG,
Demidchik YE, et al. (2011) Improving the efficiency of chemotherapeutic drugs
by the action on neuroepithelial tumors. In: Glioma - Exploring Its Biology and
Practical Relevance. Ed. Anirban Ghosh 21: 465-486.
7.
Kulchitsky VA, Potkin VI, Zubenko YS, Chernov AN,
Talabaev MV, et al. (2012) Cytotoxic effects of chemotherapeutic drugs and heterocyclic
compounds at application on the cells of primary culture of neuroepithelium
tumors. Med Chem 8: 22-32.
8.
Kulchitsky VA, Alexandrova R, Suziedelis K, Paschkevich
SG, Potkin VI (2014) Perspectives of fullerenes, dendrimers and heterocyclic
compounds application in tumor treatment. Recent Patents Nanomed 4: 82-89.
9.
Segel M, Neumann B, Hill MFE, Weber IP, Viscomi C, et al.
(2019) Niche stiffness underlies the ageing of central nervous system
progenitor cells. Nature.
10.
Korchagina D, Jaroslawski S, Jadot G, Toumi M (2019)
Orphan drugs in oncology. Recent Results Cancer Res 213: 109-142.
11.
Conter HJ, Chu QSC (2012) Wise investment? Modeling
industry profitability and risk of targeted chemotherapy for incurable solid
cancers. J Oncol Pract 8: 69.
12.
Pan J, Rostamizadeh K, Filipczak N, Torchilin VP (2019)
Polymeric co-delivery systems in cancer treatment: An overview on component
drugs’ dosage ratio effect. Molecules 24: pii: E1035.
13.
Pan J, Mendes LP, Yao M, Filipczak N, Garai S, et al.
(2019) Polyamidoamine dendrimers-based nanomedicine for combination therapy
with siRNA and chemotherapeutics to overcome multi-drug resistance. Eur J Pharm
Biopharm 136:18-28.
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