Skip to main content

Advertisement

Log in

Modeling and analysis of a virus that replicates selectively in tumor cells

  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Replication-competent viruses have shown considerable promise in overcoming the inefficient gene transduction experienced by traditional gene therapy approaches to cancer treatment. The viruses infect tumor cells and replicate inside them, eventually causing lysis. Virus particles released during lysis are then able to infect other tumor cells, and, in this way, continuous rounds of infection and lysis allow the virus to spread throughout the tumor. Motivated by this novel cancer treatment, we formulate and analyse a system of partial differential equations that is essentially a radially-symmetric epidemic model embedded in a Stefan problem. We compare three, alternative virus-injection strategies: a fixed fraction of cells pre-infected with the virus are introduced throughout the entire tumor volume, within the tumor core, or within the tumor rim. For all three injection methods, simple and accurate conditions that predict whether the virus will control the tumor are derived.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Adam, J. A. and N. Bellomo (1997). A Survey of Models for Tumor-Immune System Dynamics, Boston, MA: Birkhäuser.

    MATH  Google Scholar 

  • Aldous, D. (1989). Probability Approximations via the Poisson Clumping Heuristic, Applied Mathematical Sciences 77, Berlin: Springer-Verlag.

    MATH  Google Scholar 

  • Andjel, E. and R. Schinazi (1996). A complete convergence theorem for an epidemic model. J. Appl. Prob. 33, 741–748.

    Article  MathSciNet  MATH  Google Scholar 

  • Bischoff, J. R. et al. (1996). An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274, 373–376.

    Article  Google Scholar 

  • Boucher, Y., H. Salehi, B. Witwer, G. R. Harsh IV and R. K. Jain (1997). Interstitial fluid pressure in intracranial tumours in patients and in rodents. Br. J. Cancer 75, 829–836.

    Google Scholar 

  • Byrne, H. M. and M. A. J. Chaplain (1997). Free boundary value problems associated with the growth and development of multicellular spheroids. Eur. J. Appl. Math. 8, 639–658.

    Article  MathSciNet  MATH  Google Scholar 

  • Byrne, H. M. and M. A. J. Chaplain (1999). Necrosis and apoptosis: distinct cell loss mechanisms in a mathematical model of avascular tumour growth. J. Theor. Med. 1, 223–239.

    Google Scholar 

  • Coffey, M. C., J. E. Strong, P. A. Forsyth and P. W. K. Lee (1998). Reovirus therapy of tumors with activated Ras pathways. Science 282, 1332–1334.

    Article  Google Scholar 

  • Conger, A. D. and M. C. Ziskin (1983). Growth of mammalian multicellular tumor spheroids. Cancer Res. 43, 556–560.

    Google Scholar 

  • Cox, J. T. and R. Durrett (1988). Limit theorems for the spread of epidemics and forest fires. Stoch. Proc. Appl. 30, 171–191.

    Article  MathSciNet  MATH  Google Scholar 

  • Diekmann, O. (1978). Thresholds and traveling waves for the geographical spread of infection. J. Math. Biol. 6, 109–130.

    MATH  MathSciNet  Google Scholar 

  • Diekmann, O., J. A. P. Heesterbeek and J. A. J. Metz (1990). On the definition and the computation of the basic reproductive ratio R 0 in models for infectious diseases in heterogeneous populations. J. Math. Biol. 28, 365–382.

    Article  MathSciNet  MATH  Google Scholar 

  • Durrett, R. and S. Levin (1994). The importance of being discrete (and spatial). Theor. Popul. Biol. 46, 363–394.

    Article  MATH  Google Scholar 

  • Fowler, J. F. (1991). The phantom of tumor treatment—continually rapid proliferation unmasked. Radiother. Oncol. 22, 156–158.

    Article  Google Scholar 

  • Ganly, I., D. Kirn, G. Eckhardt et al. (2000). A phase I study of Onyx-015, an E1B-attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res. 6, 798–806.

    Google Scholar 

  • Greenspan, H. P. (1972). Models for the growth and stability of cell cultures and solid tumours. J. Theor. Biol. 56, 229–242.

    MathSciNet  Google Scholar 

  • Hall, P. (1988). Introduction to the Theory of Coverage Processes, New York: Wiley.

    MATH  Google Scholar 

  • Heise, C., A. Sampson-Johannes, A. Williams, F. McCormick, D. D. Von Hoff and D. H. Kirn (1997). ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Med. 3, 639–645.

    Article  Google Scholar 

  • Heise, C., A. Williams, J. Olesch and D. H. Kirn (1999). Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection: intratumoral spread and distribution effects. Cancer Gene Therapy 6, 499–504.

    Article  Google Scholar 

  • Jain, R. (1994). Barriers to drug delivery in solid tumors. Sci. Am. 271, 58–65.

    Article  Google Scholar 

  • Kendall, D. G. (1965). Mathematical models of the spread of infection, in Mathematics and Computer Science in Biology and Medicine, London: Medical Research Council, pp. 213–224.

    Google Scholar 

  • Kirn, D., J. Nemunaitis, J. I. Ganly et al. (1998). A phase II trial of intratumoral injection of an E1B-deleted adenovirus, ONYX-015, in patients with recurrent head and neck cancer. Proceedings of the American Society for Clinical Oncology, Abstract 391.

  • Lowe, S. W. (1997). Progress of the smart bomb cancer virus. Nat. Med. 3, 606–608.

    Article  Google Scholar 

  • Mirchandani, D., J. Zheng, G. Miller, A. Ghosh, D. Shibata, R. Cote and P. Roy-Burman (1995). Heterogeneity in intratumoral distribution of p53 mutations in human prostate cancer. Am. J. Pathol. 147, 92–101.

    Google Scholar 

  • Mollison, D. (1977). Spatial contact models for ecological and epidemic spread. J. R. Stat. Soc. B. 39, 283–326.

    MATH  MathSciNet  Google Scholar 

  • Mollison, D. (1991). Dependence of epidemic and population velocities on basic parameters. Math. Biosci. 107, 255–287.

    Article  MATH  Google Scholar 

  • Murray, J. D. (1989). Mathematical Biology, Berlin: Springer-Verlag.

    MATH  Google Scholar 

  • O’Donoghue, J. A., M. Bardies and T. E. Wheldon (1995). Relationships between tumor size and curability for uniformly targeted therapy with beta-emitting radionuclides. J. Nucl. Med. 36, 1902–1909.

    Google Scholar 

  • Oelschläger, K. (1992). The spread of a parasitic infection in a spatially distributed host. J. Math. Biol. 30, 321–354.

    Article  MATH  MathSciNet  Google Scholar 

  • Rodriguez, R., E. R. Schuur, H. Y. Lim, G. A. Henderson, J. W. Simons and D. R. Henderson (1997). Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res. 57, 2559–2563.

    Google Scholar 

  • Rubenštein, L. I. (1971). The Stefan Problem, Translations of Mathematical Monographs 27, Providence, RI: American Mathematical Society.

    Google Scholar 

  • Rubinow, S. I. (1975). Introduction to Mathematical Biology, New York: Wiley.

    MATH  Google Scholar 

  • Swabb, E. A., J. Wei and P. M. Gullino (1974). Diffusion and convection in normal and neoplastic tissues. Cancer Res. 34, 2814–2822.

    Google Scholar 

  • Thomlinson, R. H. and L. H. Gray (1955). The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549.

    Google Scholar 

  • van den Bosch, F., J. A. J. Metz and O. Kiekmann (1990). The velocity of spatial population expansion. J. Math. Biol. 28, 529–565.

    Article  MathSciNet  MATH  Google Scholar 

  • Ward, J. P. and J. R. King (1997). Mathematical modelling of avascular-tumour growth. IMA J. Math. Med. Appl. Biol. 14, 39–70.

    MATH  Google Scholar 

  • Worgall, S., G. Wolff, E. Falck-Pendersen and R. G. Crystal (1997). Innate immune mechanisms dominate elimination of adenoviral vectors following in vivo administration. Hum. Gene Ther. 8, 37–44.

    Google Scholar 

  • Wu, J. T. (1999). Mathematical modeling and analysis of replication-competent adenovirus that replicates selectively in p53-deficient tumor cells, Undergraduate thesis, Department of Chemical Engineering, M.I.T., Cambridge, MA.

    Google Scholar 

  • Wu, J. T., H. M. Byrne, D. H. Kirn and L. M. Wein (2000). Mathematical modeling of a replication-competent virus for cancer treatment: implications for design and delivery. Submitted for publication.

  • Yang, Y., Q. Li, J. Ertl and J. M. Wilson (1994). Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc. Natl. Acad. Sci. USA 91, 4407–4411.

    Article  Google Scholar 

  • Yang, G., A. Stapleton, T. Wheeler, L. Truong, T. Timme, P. Scardino and T. Thompson (1996). Clustered p53 immunostaining:a novel pattern associated with prostate cancer progression. Clin. Cancer Res. 2, 399–401.

    Google Scholar 

  • Yoon, S. S., N. M. Carroll, E. A. Chiocca and K. K. Tanabe (1998). Cancer gene therapy using a replication-competent herpes simplex virus type I vector. Ann. Surg. 228, 366–374.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lawrence M. Wein.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, J.T., Byrne, H.M., Kirn, D.H. et al. Modeling and analysis of a virus that replicates selectively in tumor cells. Bull. Math. Biol. 63, 731–768 (2001). https://doi.org/10.1006/bulm.2001.0245

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1006/bulm.2001.0245

Keywords

Navigation