The effect of cytostatics and hyperthermia on RAJI human lymphoma cells

Aim of this article is to evaluate the effect of hyperthermia on cytostatic activity of chemotherapeutic drugs carboplatin, cisplatin, oxaliplatin, carmustine, gemcitabine and etoposide in human lymphoma cell culture.

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Datum:2011
Hauptverfasser: Istomin, Yu.Р., Zhavrid, E.A., Sachivko, N.V., Alexandrova, E.N., Pocheshinsky, P.V.
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Sprache:English
Veröffentlicht: Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України 2011
Schriftenreihe:Experimental Oncology
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spelling nasplib_isofts_kiev_ua-123456789-323132025-02-23T18:22:57Z The effect of cytostatics and hyperthermia on RAJI human lymphoma cells Istomin, Yu.Р. Zhavrid, E.A. Sachivko, N.V. Alexandrova, E.N. Pocheshinsky, P.V. Original contributions Aim of this article is to evaluate the effect of hyperthermia on cytostatic activity of chemotherapeutic drugs carboplatin, cisplatin, oxaliplatin, carmustine, gemcitabine and etoposide in human lymphoma cell culture. 2011 Article The effect of cytostatics and hyperthermia on RAJI human lymphoma cells / Yu.Р. Istomin, E.A. Zhavrid, N.V. Sachivko, E.N. Alexandrova, P.V. Pocheshinsky // Experimental Oncology. — 2011. — Т. 33, № 1. — С. 19-23. — Біліогр.: 29 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/32313 en Experimental Oncology application/pdf Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
institution Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection DSpace DC
language English
topic Original contributions
Original contributions
spellingShingle Original contributions
Original contributions
Istomin, Yu.Р.
Zhavrid, E.A.
Sachivko, N.V.
Alexandrova, E.N.
Pocheshinsky, P.V.
The effect of cytostatics and hyperthermia on RAJI human lymphoma cells
Experimental Oncology
description Aim of this article is to evaluate the effect of hyperthermia on cytostatic activity of chemotherapeutic drugs carboplatin, cisplatin, oxaliplatin, carmustine, gemcitabine and etoposide in human lymphoma cell culture.
format Article
author Istomin, Yu.Р.
Zhavrid, E.A.
Sachivko, N.V.
Alexandrova, E.N.
Pocheshinsky, P.V.
author_facet Istomin, Yu.Р.
Zhavrid, E.A.
Sachivko, N.V.
Alexandrova, E.N.
Pocheshinsky, P.V.
author_sort Istomin, Yu.Р.
title The effect of cytostatics and hyperthermia on RAJI human lymphoma cells
title_short The effect of cytostatics and hyperthermia on RAJI human lymphoma cells
title_full The effect of cytostatics and hyperthermia on RAJI human lymphoma cells
title_fullStr The effect of cytostatics and hyperthermia on RAJI human lymphoma cells
title_full_unstemmed The effect of cytostatics and hyperthermia on RAJI human lymphoma cells
title_sort effect of cytostatics and hyperthermia on raji human lymphoma cells
publisher Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
publishDate 2011
topic_facet Original contributions
url https://nasplib.isofts.kiev.ua/handle/123456789/32313
citation_txt The effect of cytostatics and hyperthermia on RAJI human lymphoma cells / Yu.Р. Istomin, E.A. Zhavrid, N.V. Sachivko, E.N. Alexandrova, P.V. Pocheshinsky // Experimental Oncology. — 2011. — Т. 33, № 1. — С. 19-23. — Біліогр.: 29 назв. — англ.
series Experimental Oncology
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fulltext Experimental Oncology ��� ������ ���� ��arc����� ������ ���� ��arc�� ��arc�� �� THE EFFECT OF CYTOSTATICS AND HYPERTHERMIA ON RAJI HUMAN LYMPHOMA CELLS Yu. Р. Istomin*, E.A. Zhavrid, N.V. Sachivko, E.N. Alexandrova, P.V. Pocheshinsky N.N. Alexandrov National Cancer Center of Belarus, Minsk 223040, Belarus Aim: To evaluate the effect of hyperthermia on cytostatic activity of chemotherapeutic drugs carboplatin, cisplatin, oxaliplatin, carmustine, gemcitabine and etoposide in human lymphoma cell culture. Methods: RAJI human lymphoma cells were incubated with cytostatics at 37 °C or 42 °C and evaluated for cell culture growth. Results: The number of viable cells after incubation with the drugs (except for gemcitabine) at 42 °C for 30 min was significantly lower than at 37 °C. There were synergism of cytostatic effects of platinum drugs (carboplatin, cisplatin and oxaliplatin) with cytostatic effect of 42 °C and the summation of cytostatic effect of carmustine or etoposide with the action of hyperthermia. The thermal enhancement ratio was 3.0 for oxaliplatin, 2.0 for cisplatin, 1.8–2.4 for carboplatin. The combination of platinum drugs with gemcitabine resulted in a significant enhancement of cytostatic activity. Conclusion: Our findings suggest that a gain in sensitivity of RAJI human lymphoma cells to platinum drugs occurs at 42 °C. Key Words: RAJI human lymphoma cells, hyperthermia, thermochemotherapy. Intrinsic drug resistance of tumor cells or t�at acquired during t�e c�emot�erapy is considered to be t�e main cause of failures in t�e treatment of malignant tumors. Overcoming of t�e tumor drug resistance may open new perspectives in t�e man- agement of patients for w�om standard t�erapeutic approac�es are ineffective. To overcome t�e c�emoresistance� different p�ysicoc�emical modalities are currently used t�at can selectively en�ance t�e sensitivity of tumor cells to anticancer t�erapy. Hypert�ermia is regarded as t�e most promising modifying factor. It s�ould also take into account t�e important fact of direct damaging effect of �eat on t�e tumor. T�e clinical experience gained until now confirms t�ese t�eoretical prerequisites. Encouraging results of w�ole-body �ypert�ermia are ac�ieved in c�emo- t�erapy for disseminated melanoma [�]� metastatic sarcoma [�]� recurrent ovarian cancer [��4]� pleural mesot�elioma [5]� malignant tumors in c�ildren [6] and ot�er types of tumors [7���]. In a number of cases �ypert�ermia makes it possible to reduce t�e doses of administered cytostatics by up to 5�% wit� concur- rent en�ancement of antitumor effect and decrease of nep�rotoxic� cardiotoxic and �epatotoxic effects of t�e c�emot�erapeutic agents. In experimental models of various tumors� ampli- fication of cytostatic antitumor effect wit� increased temperature was demonstrated. Numerous studies of tumor cell cultures reported increased cytotoxicity of cyclop�osp�amide� melp�alan� ifosfamide� nitro- sourea� bleomycin� doxorubicin� platinum prepara- tions� etoposide� vincristine� taxanes� gemcitabine [����5]. T�e deat� of tumor cells induced by cyto- statics was found to rise wit� elevated temperature and prolonged duration of �eating� and t�e �ig�est- cytotoxicity was recorded wit� concurrent exposure to a c�emot�erapeutic agent and �ypert�ermia. T�e mec�anism of en�ancing antitumor activity of c�emot�erapeutic agents at elevated temperature �as not been definitively determined. T�e available findings suggest t�at permeability of cell membranes and penetration of drugs into tumor cells are improved� and t�at t�e mec�anisms of repair of primary and secondary damage of tumor cells are in�ibited [�6]. Notably� t�e results of experimental studies inves- tigating t�e interaction between �ypert�ermia and cy- tostatic drugs are quite contradictive. T�e use of vari- ous cell lines and experimental tumors� treatment regimens� temperature levels and drug concentrations makes it difficult to interpret t�e results of t�e studies. Investigation of possible t�ermal en�ancement of �uman lymp�oma cell sensitivity to cytostatic drugs used in t�e management of t�e disease is of interest for t�e development of t�ermoc�emot�erapy sc�emes for malignant lymp�omas. T�e objective of t�is study was investigation of t�e effect of �ypert�ermia on t�e cytostatic activity of c�emot�erapeutic agents used in t�e treatment of malignant lymp�oma; t�e investiga- tion was conducted on RAJI �uman lymp�oma cell line. MATERIALS AND METHODS Chemotherapeutic drugs. T�e effect of t�e following c�emot�erapeutic agents was evaluated: carboplatin �c�emocarb� Dabur P�arma Ltd.� In- dia�� oxaliplatin �eloxatin� Sanofi-Wint�rop Industria� France�� cisplatin �cytoplatin� CIPLA Ltd.� India�� carmustine �BiCNU� Bristol-�eiers Squibb� Italy�� etoposide �etoposide-Ebewe� Austria�� gemcitabine �citogem� Dr. Reddy’s Laboratories Ltd.� India�. T�e drugs were diluted wit� saline or distilled water for injections according to t�e package insert instructions� just before t�e experiment. Cell culture. T�e investigations were conducted on RAJI �uman lymp�oma cell line �Russian Collection of Cell Cultures� Cytology Institute of Russian Acad- emy of Sciences� St. Petersburg�. T�e cell culture was Received: October 28, 2010. *Correspondence: E-mail: istomin06@mail.ru Abbreviations used: IC50 — drug concentration resulting in growth inhibition by 50% vs. the control; TER — thermal enhancement ratio. Exp Oncol ���� ��� �� ����� �� Experimental Oncology ��� ������ ���� ��arc�� grown in RP�I-�64� culture medium supplemented wit� ��% fetal calf serum. Cell treatment. To perform t�e experiments� t�e cell culture was plated in culture vials� ������� cells in � ml of t�e culture medium in eac�. Twenty-four �ours later 5����� µl of cytostatic solution were added into t�e vials for different final concentrations. T�e vials wit� t�e cell culture were incubated in �eating bat� circulator EXATER� U� �Julabo� Germany� at �7 °C or 4� °C for �5 or �� min and for 48 � in t�e t�ermostat at �7 °C. After adding �.�% trypan blue to t�e suspension� live �un- stained� cells were counted in �emocytometer. T�ree vials wit� cells were used for eac� drug concentration. Regression analysis of t�e data was employed to calculate t�e rate of growt� in�ibition of t�e tu- mor cell culture �IC5� — drug concentration resulting in growt� in�ibition by 5�% versus t�e control�. T�er- mal en�ancement ratios �TER� for in�ibition of cell proliferation for eac� c�emot�erapeutic drug were calculated as IC5� for drug alone divided by IC5� for drug combined wit� �ypert�ermia [�7]. T�e values obtained were processed using stand- ard statistical met�ods of Origin 7.�. RESULTS AND DISCUSSION T�e study of RAJI �uman lymp�oma cell culture growt� demonstrated t�at t�e effect of 4� °C tem- perature was more prominent wit� increased duration of �eating. T�e �eating of t�e cells for �5 min did not actually affect t�e number of viable cells� w�ereas t�e increase in t�ermal treatment duration up to �� and 6� min resulted in t�e reduction of viable cell numbers to 64% and 4�%� respectively. Fig. � presents t�e results of RAJI �uman lym- p�oma cells incubation wit� c�emot�erapeutic agents at different concentrations in temperature settings of �7 °C or 4� °C for �5 and �� min. T�e findings sug- gest t�at examined drugs induce significant in�ibition of �uman lymp�oma cell culture growt� at �7 °C� wit� growing cytostatic effect upon increasing t�e final concentration of t�e drug in t�e culture medium. T�e calculation of cytostatic activity rate �IC5�� demonstrated t�at RAJI �uman lymp�oma cell culture at �7 °C is most sensitive to etoposide �IC5� = �.� µg/ml�� oxaliplatin �IC5� = �.� µg/ml� and cisplatin �IC5� = �.8 µg/ml�. IC5� was 8.5 µg/ml for carboplatin� �.� µg/ml for car-µg/ml for carboplatin� �.� µg/ml for car-�.� µg/ml for car-µg/ml for car- mustine and 6.5 µg/ml for gemcitabine �Table ��. Table 1. Cytostatic activity of chemotherapeutic agents at 37 оС and hy- perthermia setting Agent IC5�, µg/ml 37 °С 42 °С, 15 min 42 °С, 30 min Cisplatin 0.8 0.4 (TER = 2.0) 0.4 (TER = 2.0) Carboplatin 8.5 4.8 (TER = 1.8) 3.6 (TER = 2.4) Oxaliplatin 0.3 0.1 (TER = 3.0) 0.1 (TER = 3.0) Carmustine 9.3 8.9 (TER = 1.0) 9.2 (TER = 1.0) Gemcitabine 6.5 4.7 (TER = 1.4) 8.4 (TER = 0.8) Etoposide 0.1 0.1 (TER = 1.0) 0.1 (TER = 1.0) Incubation of RAJI �uman lymp�oma cells wit� oxaliplatin at 4� °C for �5 min resulted in significant reduction of cell number compared to �7 °C. Effective-°C. Effective-C. Effective- ness of gemcitabine and etoposide was not c�anged� and t�e en�ancement of t�e effect of carboplatin� cisplatin and carmustine at 4� °C for �5 min was ob-°C for �5 min was ob-C for �5 min was ob- served only at certain concentrations of t�e drug. Cell incubation at 4� °C for �� min significantly increased t�e efficiency of all investigated drugs� except for gemcitabine �Fig. ��. T�e calculation of cell culture growt� in�ibition using IC5� criterion and taking into account t�e reduced num- ber of cells due to t�e effect of increased temperature alone demonstrated t�at synergetic amplification of t�e cytostatic effect by �ypert�ermia occurred wit� oxali- platin� carboplatin and cisplatin: drug IC5� decreased from �.� at �7 °C to �.� µg/ml at 4� °C for oxaliplatin� from 8.5 to 4.8��.6 µg/ml for carboplatin� and from �.8 to �.4 µg/ml for cisplatin. Summation of drug and �ypert�ermia effects was observed wit� carmustine and etoposide� as drug IC5� did not c�ange. Hypert�ermic ex- posure wit� gemcitabine produced a small amplification of cell growt� in�ibition wit� �5 min duration of �eating �IC5� decreased from 6.5 to 4.7 µg/ml compared to t�at at �7 °C� or reduction of t�e effect wit� �� min duration of �eating �IC5� increased from 6.5 to 8.4 µg/ml com- pared to t�at at �7 °C�. T�e t�ermal en�ancement ratio �TER� of t�e cytostatic effect �t�e ratio of drug IC5� at �7 °C to IC5� at 4� °C� was �.� for oxaliplatin� �.� for cisplatin� �.8��.4 for carboplatin� �.� for car- mustine� �.� for etoposide. T�e TER for gemcitabine was �.4 wit� �5 min duration of �eating. T�e increase in �eating duration up to �� min resulted in gemcitabine effect reduction �see Table ��. T�e differences between t�e effects at t�e temperatures of �7 °C and 4� °C for all platinum preparations were statistically significant. T�e data obtained suggest t�at lymp�oma cells growt� in�ibition by alkylating c�emot�erapeutic agents carboplatin� cisplatin� oxaliplatin� carmustine and plant-derived drug etoposide increases under �ypert�ermia. For platinum drugs synergetic activ- ity wit� �ypert�ermia was observed� for carmustine or etoposide t�ere was t�e summation of cytostatic effects of drug and �ypert�ermia. It s�ould be noted t�at t�ere are contradictory reports about t�e interaction of �ypert�ermia and gemcitabine. Simultaneous application of gemcitabine and �eating led to t�e decreased cytotoxicity [�6� ��]� �ad no influence on cytotoxicity [��] or augmented cytotoxic effect of t�e drug [��� �8� ��]. Our data did not allow to consider gemcitabine as a promising drug for t�ermoc�emot�erapy of lymp�omas. But as gem- citabine in combination wit� platinum drugs is used for t�e treatment of refractory lymp�oma� we investigated t�e effect of �ypert�ermia on t�e cytostatic effect of t�is combination. T�e data presented on Fig. � indicate t�at t�e combination of platinum drugs wit� gemcitabine �5 µg/ml� at t�e temperature of �7 °C results in signifi- cant in�ibition of RAJI �uman lymp�oma cell culture growt�� t�e effect of cytostatics increasing wit� t�e rise of t�e final concentration of platinum agents. A convincing corroboration of antitumor effect en- �ancement is t�e reduction of drug IC5�. W�ile IC5� for cisplatin alone was �.8 µg/ml� for carboplatin alone Experimental Oncology ��� ������ ���� ��arc����� ������ ���� ��arc�� ��arc�� �� 8.5 µg/ml� and for oxaliplatin alone �.� µg/ml �see Table ��� it decreased to �.�6 µg/ml for cisplatin wit� gemcitabine �5 µg/ ml�� to �.5 µg/ml for carboplatin wit� gemcitabine� and to �.�� µg/ml for oxaliplatin wit� gemcitabine �Table ��. T�us� cytostatic activity of platinum preparations in combination wit� gem- citabine increased ��-fold for cisplatin� �7-fold for carboplatin� and ��-fold for oxaliplatin. Gemcitabine alone �5 µg/ml� at �7 °C reduced t�e number of RAJI �uman lymp�oma cells only �-folds. T�us� we can conclude about t�e synergistic action of gemcitabine wit� t�e platinum drugs at �7 °C. Incubation of t�e cells wit� platinum drugs in com- bination wit� gemcitabine at 4� °C for �5 min virtually did not affect t�e cytostatics activity compared to t�at at �7 °C. T�e increased duration of cell incubation at 4� °C up to �� min led to t�e reduction in t�e number of viable cells compared to t�e numbers observed at �7 °C �Fig. ��. T�e calculation of cytostatic effect rates for platinum drugs� taking into account t�e re- duced number of cells due to t�e effect of increased temperature alone� demonstrated t�at it was t�e case of summation of cytostatic effect of platinum drugs wit� gemcitabine and cytostatic effect of �ypert�ermia as drug’s IC5� did not actually c�ange after exposure to �ypert�ermia �see Table ��. Table 2. Cytostatic activity of platinum drugs in combination with gem- citabine Drugs IC5�, µg/ml 37 °С 42 °С, 15 min 42 °С, 30 min Gemcitabine + cisplatin 0.06 0.06 0.05 Gemcitabine + carboplatin 0.5 0.5 0.4 Gemcitabine + oxaliplatin 0.03 0.03 0.03 0 1 5,0 0 20 40 60 80 100 120 cisplatin C el ln um be r, % Concentration, µg/ml 0 10 50 0 20 40 60 80 100 120 carmustine C el ln um be r, % Concentration, µg/ml 0 10 50 10 20 30 40 50 60 70 80 90 100 110 120 gemcitabine C el ln um be r, % Concentration, µg/ml 0 10 50 -80 -60 -40 -20 0 20 40 60 80 100 120 carboplatin C el ln um be r, % Concentration, µg/ml 0,0 0,2 0,4 0,6 0,8 1,0 10 20 30 40 50 60 70 80 90 100 110 120 etoposide C el ln um be r, % Concentration, µg/ml 0,0 0,2 0,4 0,6 0,8 1,0 0 20 40 60 80 100 120 oxaliplatin C el ln um be r, % Concentration, µg/ml 37 °C 42 °C, 15 min 42 °C, 30 min Fig. 1. Cytostatic effect related to drug concentration and cell incubation temperature �� Experimental Oncology ��� ������ ���� ��arc�� 0,0 0,1 0,50 -40 -20 0 20 40 60 80 100 120 gemcitabine+oxaliplatin Concentration of oxaliplatin, µg/ml 0,0 0,1 0,50 -60 -40 -20 0 20 40 60 80 100 120 gemcitabine+cisplatin Concentration of cisplatin, µg/ml 0 1 5,0 -40 -20 0 20 40 60 80 100 120 gemcitabine+carboplatin Concentration of carboplatin, µg/ml Ce lln um be r, % Ce lln um be r, % Ce lln um be r, % Fig. 2. T�e impact of �ypert�ermic exposure �4� °C� �5 or �� min� and gemcitabine �5 µg/ml� on cytostatic effect of platinum drugs T�e results of t�e study allowed to assert t�at growt� in�ibition of RAJI cells by carboplatin� cisplatin� oxali- platin� carmustine and etoposide was increased by t�e exposure to 4� °C for �� min. Summation of drug and �ypert�ermia cytostatic effects was observed for car- mustine and etoposide� synergic effect — for all plati- num drugs. T�e t�ermal en�ancement ratio was �.� for oxaliplatin� �.� for cisplatin and �.8��.4 for carboplatin. T�e combination of platinum agents wit� gem- citabine at �7 °C produces a synergic effect of t�e cytostatics. In suc� combination� IC5� of platinum drugs was reduced ��-fold for oxaliplatin� ��-fold for cisplatin� �7-fold for carboplatin. Incubation of t�e cells wit� platinum preparations in combination wit� gem- citabine at 4� °C for �� min causes a reduction in t�e number of viable cells compared to cell incubated at �7 °C� w�ic� is a result of summation of cytostatic effects of drugs and �ypert�ermia. T�e obtained results give grounds to continue t�e study on animal models wit� feasible prospects of clinical application. REFERENCES 1. Zhavrid EA, Osinsky SP, Fradkin SZ. Hyperthermia and hyperglycemia in oncology. Kiev: Naukova dumka, 1987. 256 p. (In Russian). 2. Westermann AM, Wiedemann GJ, Jager E, et al. 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