  Chemotherapy is one of the most important therapeutic options used to treat
human cancers, either alone or in combination with radiation therapy and
surgery. Recent studies have indicated that intra-tumoural heterogeneity has a
significant role in driving resistance to chemotherapy in many human
malignancies. Multiple factors including the internal cell-cycle dynamics and
the external microenvironement contribute to the intra-tumoural heterogeneity.
In this paper we present a hybrid, multiscale, individual-based mathematical
model, incorporating internal cell-cycle dynamics and changes in oxygen
concentration, to study the effects of delivery of several different
chemotherapeutic drugs on the heterogeneous subpopulations of cancer cells with
varying cell-cycle dynamics. The computational simulation results from the
multiscale model are in good agreement with available experimental data and
support the hypothesis that slow-cycling sub-populations of tumour cells within
a growing tumour mass can induce drug resistance to chemotherapy and thus the
use of conventional chemotherapy may actually result in the emergence of
dominant, therapy-resistant, slow-cycling subpopulations of tumour cells. Our
results indicate that the appearance of this chemotherapeutic resistance is
mainly due to the inability of the administered drug to target all cancer cells
irrespective of the stage in the cell-cycle they are in i.e. most
chemotherapeutic drugs target cells in a particular phase/phases of the
cell-cycle, and hence always spare some cancer cells that are not in the
targeted cell-cycle phase/phases. The results also suggest that this
cell-cycle-mediated drug resistance may be overcome by using multiple doses of
cell-cycle, phase-specific chemotherapy that targets cells in all phases and
its appropriate sequencing and scheduling.
