One of the most common mechanisms for drug resistance in lymphoma is the up-regulation of P-glycoprotein.This up-regulation
confers multi-drug resistance on the cell. P-glycoprotein is a membrane pump that can transport multiple substrates out of
the cell where they have no effect. Substates for this pump often are structurally unrelated but include many of the natural
products or their derivatives (Table 2).
Table 2. Drugs affected by MDR
P-glycoprotein normally is expressed in tissues such as the kidney, adrenal gland, lung, liver and colon, which most likely
accounts for the de novo resistance of cancers arising from these organs. Drugs that are affected by this mechanism include
steroids, vinca alkaloids, anthracyclines and the taxanes. Resistance to one drug may convey resistance to several others.
It has been shown that lymphoma cells have lower levels of p-glycoprotein prior to treatment and that these levels increase
at relapse. In addition, dogs that have high levels pre-treatment have been found to have lower response rates.
Prednisone is capable of upregulating p-glycoprotein, which may explain the decreased response rates in those patients pre-treated
There are other mechanisms of resistance important to lymphoma patients. These would include increased DNA repair, inactivation
of drugs, increase in drug catabolism or altered drug targets. Resistance to alkylating agents often is acquired by increased
DNA repair or drug inactivation. However, resistance to one alkylating agent does not confer resistance to others.
Employing different alkylating agents is a strategy often seen in the design of rescue protocols for lymphoma dogs. Resistance
to anti-metabolites can be conferred by alteration of target enzymes, increased drug catabolism and decreased drug activation.
Commonly used rescue protocols
For dogs t treated with a CHOP-L type of protocol and then taken off treatment for a while, an effective strategy may be re-induction
with a similar CHOP-L protocol. In dogs that were treated with VELCAP-S, it was reported that 87 percent achieved a second
remission when re-induced with a similar protocol. (Moore 2001).
For dogs achieving a second remission, the decision that must be made is whether to treat them with a short-term protocol
again or continue them on one that includes a maintenance phase. In our clinic, dogs that relapse prior to one year receive
maintenance chemotherapy while those that relapse after one year repeat a short-term protocol.
For those dogs that finish a second protocol and subsequently relapse, it is possible to consider using a CHOP-L protocol
a third time. It should be kept in mind that the cumulative dose of doxorubicin is 180 mg/m2, so that an alternative drug
such as mitoxantrone or actinomycin-D should be used instead, once the cumulative dose is reached.
For dogs that have failed a COP protocol, single-agent doxorubicin or actinomycin-D may be an effective alternative. In one
study, 25 percent of dogs had either a complete or partial response to doxorubicin with a mean remission time of 134 days
(Leifer 1981). However, resistance to vincristine or prednisone also may confer resistance to doxorubicin or actinomycin-D,
due to up-regulation of P-glycoprotein. \When used s a single agent, doxorubicin is given once every 21 days, up to a cumulative
dose of 180 mg/m2.
Mitoxantrone is considered inferior to doxorubicin for the treatment of canine lymphoma, so its use has been limited to a
substitute for doxorubicin for those dogs that have pre-existing cardiac disease or once the cumulative limit is reached.
Despite the similarities of these drugs, it has been shown that these two drugs can have different mechanisms of action and
resistance, so that mitoxantrone may be effective when doxorubicin is not.
Seven out of 15 dogs that had previously received doxorubicin achieved a complete response with mitoxantrone for a median
of 84 days (Madewell, 1998). Mitoxantrone has the advantage of not having a cumulative limit, so that longer-term treatment
is possible. Mitoxantrone also given intravenously once every 21 days.