Overcoming tumor hypoxia as a barrier to radiotherapy, chemotherapy and immunotherapy in cancer treatment

Figures & data

Figure 1 Hypoxic tumor regions lie further from feeding vessels.

Figure 2 Tumor pO₂ measurements from published clinical studies documenting the hypoxic state of various solid tumors.

Note: Data from Vaupel et al.⁴

Abbreviation: pO₂, pressure of oxygen.

Figure 3 Hypoxyprobe™-1IHC staining in human ovarian tissue sections. The A–C, and D–E, respectively represent three separate tissue sections from two ovarian tumors; Percent positive staining for Hypoxyprobe™-1 is indicated. All pictures are 20× magnification.

Note: IHC staining performed by the Tissue Acquisition and Cellular/Molecular Analysis Shared Resource (TACMASS); the core at the University of Arizona Cancer Center and analysis done by Dr Amanda Baker.

Abbreviation: IHC, immunohistochemistry.

Table 1 Effect of oxygen tension on cancer therapya

Critical O2 tension (mmHg)	Function or parameter observed
30–35	Effectiveness of certain (passive) immunotherapies
15–35	Cell death with PDT
25–30	Cell death on exposure to χ- and γ-radiation
10–20	Binding of hypoxia markers
1–15	Proteome changes
0.2–1	Genome changes

Note:

a Reformatted from Höckel M, Vaupel P, Tumor hypoxia: definitions and current clinical, biologic, and Molecular Aspects. J Natl Cancer Inst. 2001;93(4):266–276, by permission of Oxford University Press.¹⁵

Abbreviation: PDT, photodynamic therapy.

Table 2 Cancer drugs less effective in hypoxia

Drug	Type of drug	References
5-Fluorouracil	Antimetabolite	^Citation24
Actinomycin D	Antitumor antibiotic	^Citation20, ^Citation21, ^Citation24
Bleomycin	Antitumor antibiotic	^Citation20, ^Citation21, ^Citation24
Carboplatin	Alkylating agent	^Citation24
Cisplatin	Alkylating agent	^Citation25
Docetaxel	Plant alkaloid, mitosis inhibitor, taxane	^Citation21
Doxorubicin	Anthracycline antibiotic	^Citation24
Etoposide	Plant alkaloid, topoisomerase II inhibitor	^Citation24
Gemcitabine	Antimetabolite	^Citation24
Irinotecan	Plant alkaloid, topoisomerase I inhibitor	^Citation22
Melphalan	Alkylating mustard analog	^Citation22
Methotrexate	Antimetabolite	^Citation24
Oxaliplatin	Alkylating agent	^Citation25
Procarbazine	Alkylating agent	^Citation20, ^Citation21
Sorafenib	Multikinase inhibitor, antiangiogenic	^Citation22
Streptonigrin	Antitumor antibiotic	^Citation21
Temozolomide	Alkylating agent	^Citation21
Thiotepa	Alkylating agent	^Citation20
Vincristine	Plant alkaloid, vinca alkaloid	^Citation20, ^Citation21
VP-16	Plant alkaloid, topoisomerase II inhibitor	^Citation20

Figure 4 DDFPe carries more oxygen than PFOBe or PFDe.

Note: Reproduced with permission from Taylor & Francis Ltd, In vitro comparison of dodecafluoropentane (DDFP), perfluorodecalin (PFD), and perfluoroctylbromide (PFOB) in the facilitation of oxygen exchange. Artif Cells Blood Substit Immobil Biotechnol. Copyright © 2009 Taylor & Francis Ltd.

Abbreviations: DDFPe, dodecafluoropentane emulsion; PFOBe, perfluorooctylbromide; PFDe, perfluorodecalin emulsion.

Table 3 Comparison of safety profile of NVX­108 vs Fluosol in clinical studies as a radiosensitizer

Agent	w/vol % FC	Dose/kg (gFC/kg)	Indication	Frequency dosing (total doses)	Acute complications
NVX-108^Citation82	2	0.1 mL (0.002)	GBM	5 × week, 30 doses	The only definite TEAE was a brief episode of dizziness that occurred in one patient. Two patients had radiation necrosis that was deemed probably related to NVX-108.
Fluosol^Citation64	20	8.0 mL (1.6)	Head and neck	1 × week, five doses	Four of 15 patients experienced flushing, warmth or chest pressure with the first dose. One patient had fever up to 38.5°C. Increased liver enzymes, alk phos, SGOT and SGPT in 8/15 patients. Alk phos remained elevated for about 3 months.
Fluosol^Citation65	20	8.0 mL (1.6)	GBM	1 × week seven doses	2/3rds of patients had allergic reaction, 11 of 18 patients had elevations in alk phos, SGOT and SGPT. Liver function abnormalities persisted through treatment. Most resolved by 3 months.
Fluosol^Citation66	20	10.33–15.50 mL (2.1–3.1)a	Recurrent GBM	1 × week six doses	98 patients were enrolled. Alterations of vital signs occurred in sixty-eight subjects (69.4%) within 5 to 10 minutes of Fluosol test dose or infusion. At least one nonlethal Fluosol-related adverse event occurred in 32% of the 98 subjects evaluable for safety (76 occurrences). Most frequently reported were Fluosol-related nausea/vomiting (16 occurrences), flushing, dyspnea, and chest tightness/chest pain (seven occurrences each) and back pain (four episodes). Six events were grade 3.

Note:

a The dose reported in this study was converted from the cumulative dose 400–600 mL per M² assuming 60 kg body weight corresponds to 1.55 M².

Abbreviations: GBM, glioblastoma multiforme; FCs, fluorocarbons; SGOT, serum glutamic oxaloacetic transaminase; SGPT, serum glutamic pyruvic transaminase; TEAE, treatment-emergent adverse event.

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