The impact of γ-irradiation on the induction of bystander killing by genetically engineered ovarian tumor cells: implications for clinical use

Our plain-English summary of The impact of γ-irradiation on the induction of bystander killing by genetically engineered ovarian tumor cells: implications for clinical use, by J. Zweiri, S.E. Christmas (Cancer Cell International, 2017).

The study

• Authors: J. Zweiri, S.E. Christmas
• Journal: Cancer Cell International
• Published: 2017;17:96
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Cellular based therapeutic approaches for cancer rely on careful consideration of finding the optimal cell to execute the cellular goal of cancer treatment. Cell lines and primary cell cultures have been used in some studies to compare the in vitro and in vivo efficacy of autologous vs allogeneic tumour cell vaccines.

Methods: This study examines the effect of γ-irradiation on a range of tumor cell lines in conjunction with suicide gene therapy of cancer. To determine the efficacy of this modality, a series of in vitro and in vivo experiments were conducted using genetically modified and unmodified tumor cell lines.

Results: Following co-culture of HSV-TK modified tumor cells and unmodified tumor cells both in vitro and in vivo we observed that the PA-STK ovarian tumor cells were sensitive to γ-irradiation, completely abolishing their ability to induce bystander killing of unmodified tumor cells. In contrast, TK-modified human and mouse mesothelioma cells were found to retain their in vitro and in vivo bystander killing effect after γ-irradiation. Morphological evidence was consistent with the death of PA-STK cells being by pyknosis after γ-irradiation. These results suggest that PA-STK cells are not suitable for clinical application of suicide gene therapy of cancer, as lethal γ-irradiation (100 Gy) interferes with their bystander killing activity. However, the human mesothelioma cell line CRL-5830-TK retained its bystander killing potential after exposure to similarly lethal γ-irradiation (100 Gy). CRL-5830 may therefore be a suitable vehicle for HSV-TK suicide gene therapy.

Conclusions: This study highlights the diversity among tumor cell lines and the careful considerations needed to find the optimal tumor cell line for this type of suicide gene therapy of cancer.

In plain English

This laboratory study tested whether tumour cells carrying the herpes simplex virus thymidine kinase (HSV-TK) suicide gene still kill neighbouring unmodified cells (the "bystander effect") after lethal gamma-irradiation. The authors mixed TK-modified and unmodified cells with 50 micromolar ganciclovir, and treated BALB/c mice bearing intraperitoneal AB1 mesothelioma tumours (45 mice, nine groups of five). After 100 Gy, the human ovarian teratocarcinoma line PA-STK lost bystander killing (significantly less efficient than unirradiated cells at a 50:50 ratio, P = 0.04), and over 90% of irradiated PA-STK cells died by 18 hours, which the authors interpreted as pyknosis rather than apoptosis. Mouse mesothelioma AE17-STK and human mesothelioma CRL-5830-TK cells retained bystander killing after 100 Gy (no significant difference, P greater than 0.45 at all ratios). In mice, unirradiated AE17-STK plus ganciclovir gave smaller tumours than the three control groups (P = 0.03); the irradiated AE17-STK group showed a smaller reduction, not statistically significant against the unirradiated group (P = 0.56). The authors concluded PA-STK cells are poor mediators of bystander killing while CRL-5830TK may be effective. The work concerns gene therapy, not asbestos.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study: in vitro cell-line experiments combined with an in vivo mouse tumour experiment
• Who was studied: Human and mouse tumour cell lines (human mesothelioma CRL-5915, CRL-5820, CRL-5830; mouse mesothelioma AB1, AE17, AC29; human ovarian teratocarcinoma PA-1 and PA-STK; ovarian OVC-432, SKOV-3, OIB; HL-60 control) plus 45 female BALB/c mice bearing intraperitoneal AB1 mesothelioma tumours
• Exposure: Gamma-irradiation at 100 Gy (and a 1-100 Gy dose range for PA-STK cells) of HSV-TK gene-modified tumour cells, combined with ganciclovir (50 micromolar in vitro; 2 mg per mouse daily for 5 days in vivo)
• Main results:
  • Irradiated PA-STK cells were significantly less efficient than unirradiated PA-STK cells at mediating bystander killing of PA-1 cells at a 50:50 ratio, at both cell densities tested (P = 0.04)
  • Mouse mesothelioma AE17-STK and human mesothelioma CRL-5830-TK cells retained bystander killing after 100 Gy, with no significant difference from unirradiated cells
  • Over 90% of irradiated PA-STK cells had died by 18 hours after irradiation, whereas control OVC-432 cells survived beyond 48 hours
  • Cytospin histology of irradiated PA-STK cells was interpreted as death by pyknosis/necrosis rather than apoptosis
  • In mice, unirradiated AE17-STK plus ganciclovir (Group 4) produced significantly smaller tumours than the three control groups (P = 0.03); the irradiated AE17-STK plus ganciclovir group (Group 5) showed a smaller reduction than Group 4, not statistically significant (P = 0.56)
  • In mice, unirradiated PA-STK plus ganciclovir gave a detectable anti-tumour effect and irradiated PA-STK did not (P values 0.50 and 0.6 versus PBS controls); live and irradiated CRL5830-STK with ganciclovir both gave a detectable effect (P values 0.05 and 0.06)
  • Reported ganciclovir sensitivities: PA-STK IC50 of 20 mM, AE17-STK 3 mM, CRL5830-TK 1 mM
• The authors' conclusion: The authors concluded that PA-STK ovarian tumour cells are poor mediators of bystander killing and may not be suitable for future clinical trials, while CRL-5830TK human mesothelioma cells may be effective inducers of bystander killing, retaining this ability after lethal irradiation
• Limitations the authors state:
  • The authors state the mechanism of the greater radiosensitivity of PA-1 and PA-STK cells is unclear
  • The authors note that only a limited inference can be drawn from the cell-death data
  • The authors state further developments are needed, including disease models in higher vertebrates adequately representative of human malignancies

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

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