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Editorial |
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 [T. H. D., W. G. M.], and Departement d’Oncologie-Radiotherapie, Centre Hospitalier Lyon-Sud, Pierre-Benite, France [F. M.]
Gemcitabine2 is a pyrimidine analogue of deoxycytidine with a wide range of antitumor activity against solid tumors (1) . In particular, it has shown promising results as a single agent in cancers of the breast, head and neck, bladder, ovary, lung, and pancreas. Response rates have been reported in the range of 16–27% (1, 2, 3) . When used alone as a single agent (at standard doses of 1000 mg/m2 ), the most consistent toxicity is mild hematological suppression. Nonhematological toxicities consist of reversible elevations of transaminases, skin rash, and fatigue (4) . Gemcitabine enters cells by a facilitated nucleoside transport mechanism and undergoes phosphorylation by deoxycytidine kinase. Phosphorylation leads to 5'-diphosphate (dFdCDP) which inhibits ribonucleotide reductase with a subsequent decrease in the pools of dATP, dCTP, dGTP, and dTTP. A second metabolite, 5'-triphosphate (dFdCTP) is formed by additional phosphorylation and inhibits DNA polymerase activity. Inhibition of DNA synthesis may be attributable to decreases in the deoxynucleotide pools as well as interference with chain elongation (5 , 6) .
Even at very low concentrations, gemcitabine has been shown to be a powerful radiation sensitizer (7) . At doses well below those used to produce cytotoxicity, radiation enhancement ratios as high as 1.6 have been observed (8) . Because the active metabolite of gemcitabine, dFdCTP, remains intracellularly for long periods of time (from hours to days after administration), it is an intriguing choice for study as a radiosensitizer. In vitro experiments with brief (2-h) exposures to 3 µM concentrations of gemcitabine plus radiation, delivered 24–48 h later, have shown results equivalent to continuous incubation with gemcitabine plus radiation (9) .
The mechanisms of radiation sensitization by gemcitabine have not been fully elucidated. However, it does appear that the metabolite dFdCDP is responsible for radiation sensitization, whereas dFdCTP levels seem to correlate well with cytotoxicity (8 , 10 , 11) . The critical event in radiation sensitization appears to be inhibition of ribonucleotide reductase by dFdCDP that leads to decreases in deoxynucleotide triphosphate pools. In addition to reduction of deoxynucleotide triphosphate pools, radiosensitization appears to depend on cell cycle phase with the greatest degree of sensitization occurring for S-phase cells (8 , 9 , 11, 12, 13) . It has also been hypothesized that radiosensitization by gemcitabine is the result of lowering of the threshold for radiation-induced apoptosis. It has been shown in vitro that gemcitabine given concurrently with radiation, at doses that produce an enhancement ration of 1.8, produces no excess of DNA double-strand breaks or a corresponding decrease in damage repair (9 , 14) . This has led to the hypothesis that although the primary lesion produced by radiation is not increased in number, the results of the lesion are somehow enhanced. An increase in cellular death by apoptosis seemed a likely candidate.
In this issue of Clinical Cancer Research, Dr. Lawrence et
al. (15)
explore this issue of apoptosis as a
mechanism of gemcitabine radiosensitization. What they show, quite
convincingly, is that radiosensitization with gemcitabine occurs by
both the apoptotic and nonapoptotic pathways, depending on the
predominant mode of death intrinsic to the cell line being studied. An
important methodological point that allowed them to arrive at this
conclusion was their use of a clonogenic assay rather than a short-term
end point, such as dye uptake or growth inhibition. A short-term end
point may have led the authors to the conclusion that HT29 cells are
radiosensitized by gemcitabine by an increase in the apoptotic pathway,
whereas the other cell lines had relatively little radiosensitization,
as demonstrated by few dead cells at short time intervals. This was
clearly not the case when a clonogenic assay was performed. They have
effectively made the point that radiosensitization occurs in all three
cell lines but with varying degrees of apoptosis as a fraction of the
total clonogenic death. The use of three different cell lines was also
an excellent technique for illustrating the possibility of differences
in the importance of apoptosis as a method of radiosensitization of
various tumors. A more simple design with one cell line (HT29 cells)
and the addition of caspase inhibition, as done in this study, could
have led to the conclusion that apoptosis is crucial to radiation
sensitization. In addition, this paper points out a common
misconception. It is evident that the mutations responsible for
malignant transformation of cells also often impair the ability of
cells to undergo apoptosis. It is believed by some that this is a
mechanism of resistance to genotoxic agents because death from these
agents occurs predominantly by apoptosis. Furthermore, agents that
override this defect in apoptosis should restore a treatment-responsive
state to the cell. The work by Lawrence et al.
(15)
shows that this is indeed a misconception and that
cell death occurs according to the mode of death intrinsic to the cell
line. This paper has made a significant contribution to clarifying the
role of apoptosis in gemcitabine- mediated radiosensitization and a
graphic representation of our current understanding is shown in Fig. 1
.
|
Despite all of the advances in our understanding of the mechanisms behind the potent radiation-sensitizing properties of gemcitabine, there remains a paucity of clinical data to document any clinically meaningful gain in the therapeutic ratio. Because of radiosensitization of both tumor and normal tissues, the therapeutic window is extremely narrow. Many investigators are attempting to define the optimal dosing and schedule for concurrent gemcitabine and radiation therapy. However, significant toxicity with the combination of the two modalities has been seen. Both gemcitabine dose and radiation portal volume appear to play an important role in the observed toxicities. One Phase II study conducted on stage III non-small cell lung cancer patients used weekly gemcitabine doses of 1000 mg/m2 /week for 6 weeks with concurrent thoracic radiation therapy. The trial was closed after only 8 patients were enrolled because of significant pulmonary and esophageal toxicities (17) . Although demonstrating respectable response rates, a Phase I trial of concurrent gemcitabine and daily radiation for unresectable head and neck cancer revealed similar unacceptable toxicity with weekly doses of 300 mg/m2 /week (18) . All patients required gastrostomy tubes for feeding, and two patients experienced grade 4 late complications (deep ulceration and esophageal stricture). De-escalation of dose reveals that the maximum tolerated dose may fall somewhere in the range of 10–50 mg/m2 /week. A Phase I trial of twice weekly concurrent gemcitabine and radiation for unresectable pancreatic cancer established 40 mg/m2 twice weekly as the maximally tolerated dose. Dose-limiting toxicities of nausea, vomiting, neutropenia, and thrombocytopenia were seen at the 60 mg/m2 twice weekly dose level (19) .
There is convincing Phase I/II data that gemcitabine is an exciting new agent for treatment of many human malignancies. Unfortunately, there have been relatively few published reports on the long-term side effects with concurrent gemcitabine and radiation therapy. What little data we have does seem to point to alarming normal tissue toxicities of the same magnitude as the preclinical predictions of radiation enhancement. We would submit that because of the apparent narrow therapeutic index, concurrent gemcitabine and radiation therapy should be viewed with a healthy skepticism and should, at present, only take place on appropriate Phase I/II protocols.
FOOTNOTES
1 To whom requests for reprints should be
addressed, at Department of Radiation Oncology, University of
Pennsylvania School of Medicine, 3400 Spruce Street, Philadelphia, PA
19104. 
2 The abbreviation used is: gemcitabine,
2',2'-difluorodeoxycytidine.
Received 11/13/00; accepted 11/15/00.
REFERENCES
Key Article
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  B. Pauwels, A. E.C. Korst, F. Lardon, and J. B. Vermorken Combined Modality Therapy of Gemcitabine and Radiation Oncologist, January 1, 2005; 10(1): 34 - 51. [Abstract] [Full Text] [PDF]
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