Blood Vessel Growth Inhibitors Mediate Negative Side Effects of Chemotherapy

Doctors and researchers have observed an improvement in the survival rate of cancer patients when they are given a combination of a chemotherapeutic drug (cancer-killing drug) and an antiangiogenic drug (a drug that inhibits the growth of new blood vessels). This combination treatment seems to give patients a better chance of surviving than just chemo alone. It has not been clear why antiangiogenic drugs help patients undergoing chemotherapy, but cancer researchers have recently published a study in PNASProceedings of the National Academy of Sciences that sheds some light on the matter.

Chemotherapeutic Drugs
Cancer chemotherapy involves the administration of toxic chemicals that are intended to target and kill cancer cells. Unfortunately, no chemotherapeutic agent has perfect selectivity for malignant cells, so the rest of the body is slowly poisoned even as the chemicals work to kill tumors. For this reason, chemotherapy is usually very difficult for a cancer patient. A substantial number of patients can actually die because of chemo’s negative side effects.

Here are a couple of examples of chemotherapeutic drugs – these are the ones used in this study.

cyclophosphamide and carboplatin chemotherapy drugs chemical structure

Antiangiogenic Drugs
The second type of drug discussed in this study is an antiangiogenic drug. Unlike chemo drugs, antiangiogenics aren’t particularly toxic to cells (cancerous or non). Instead, they act to prevent the growth of new blood vessels (arteries, capillaries, and veins).

veins capillaries arteries antiangiogenic drugsBlood vessel growth has an interesting role in cancer. Tumor cells are notorious for being able to get new capillaries to grow toward them; these provide nutrient-rich blood to help the cancer cells thrive. Thus you can imagine that an antiangiogenic drug would make it harder for a tumor to grow, since it would have a difficult time getting new blood supplies to come its way. But slowing tumor growth is not the same as actually killing tumor cells.

Here is an example of an antiangiogenic drug – this is sunitinib, the drug used in this study.

sunitinib inhibits growth of blood vessels anti cancer

Effect of Each Drug On Its Own
Chemo drug: carboplatin. Some mice with cancerous tumors were treated with carboplatin (and nothing else), and – sadly – about 80% of them died within 10 days, apparently from the side effects of this drug. Over the 10 days, their tumors had been shrinking though.

carboplatin anticancer chemotherapy toxicity

Antiangiogenic drug: sunitinib. Some more mice with cancerous tumors were treated with sunitinib (and nothing else). After 10 days, they were all still alive, though their tumors hadn’t shrunk at all.

antiangiogenic drug sunitinib cancer treatment

Effect of the Two Drugs in Combination
The researchers gave tumor-bearing mice sunitinib for 5 days. Then they took the mice off of this antiangiogenic drug and gave them carboplatin for the next 5 days.

The mice that had this 5-day treatment with sunitinib prior to initiation of chemotherapy with carboplatin had a better survival rate than those not pretreated with sunitinib. Furthermore, the combined sunitinib + carboplatin treatment led to greater tumor shrinkage than just carboplatin with no pretreatment.

sunitinib carboplatin cancer chemotherapy

Mechanism of Action
Tumor cells are able to attract a blood supply in their direction by causing an increase in the levels of a protein called VEGFvascular endothelial growth factor. The presence of this protein signals the body to grow new blood vessels. Cancer patients often have measurably high levels of VEGF circulating in their bodies, and these elevated levels can impair the function of several tissues and organs. One of the things too much VEGF does is prevent the production of blood cells in bone marrow.

The scientists performing this mouse study found that chemotherapy (with carboplatin) exacerbates the effects of the already-high levels of VEGF, often resulting in a fatal loss of bone marrow function.

Antiangiogenic drugs like sunitinib are able to block VEGF. Therefore, pretreatment of the mice with VEGF-blocking sunitinib served to protect bone marrow from the upcoming chemotherapy.

Take-Away Message
This study suggests that pretreatment with antiangiogenic drugs before chemo drugs is more effective than the traditional concurrent treatment with both drugs.

Citation:
Zhang, D., Hedlund, E., Lim, S., Chen, F., Zhang, Y., Sun, B., & Cao, Y. (2011). Antiangiogenic agents significantly improve survival in tumor-bearing mice by increasing tolerance to chemotherapy-induced toxicity Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1016220108

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5 Responses to Blood Vessel Growth Inhibitors Mediate Negative Side Effects of Chemotherapy

  1. David P says:

    I very much enjoyed the article.

    One little (presentation) nitpick: shouldn’t the green and yellow backgrounds be reversed in the combination picture? Otherwise it looks like it is the exact reverse from what you say it is. Makes it clearer anyway.

  2. Adam L. says:

    Good post!

    The administration of an antiangiogenic drug makes sense, given the propensity of tumor cells to grow new blood vessels, but I didn’t know it had to do with the circulating protein and bone marrow growth. Interesting stuff!

  3. milkshake says:

    This is a great practical finding but a poor science.

    A convincing proof of mechanism would be if they had used a pure VEGF antibody. Human form of VEGF antibody is sold as Avastin, (I don’t know if the mice form is available).

    The problem is, Sutent is a very dirty multikinase inhibitor: In a panel of known 450+ kinases, it looks like Sutent inhibits about one third of the entire human kinome. Apart from VEGF and PDGF it also inhibits KIT, Src, CDKs and many other important cancer targets. Sutent has paradoxical anti-apoptoptosis effects: Sutent is strongly protective in retinal ganglion cells (RGCs, a type of specialised neuron in the eye) , preventing them from dying. Since the structural requirements for anti-VEGF and anti-PDGF activity are well understood, we made Sutent analogs without VEGF and PDGF activity. Some of these analogs were far more protective and less toxic than Sutent in RGCs. This confirms that at least with RGCs the protective effects of Sutent on survival has nothing to do with anti-angiogenesis. Instead it looks like activation of angiogenesis-unrelated signalling pathway combined with inhibition of another one is responsible for the RGC pro-survival effect.

    • Yeah, that would be interesting – to use Avastin instead of sunitinib. You clearly know more about this than me, so I wonder what you think about the details of their study that I didn’t include in this summary (not sure whether you got a chance to read their article or not).

      They transfected human VEGF cDNA into the mouse cancer cell line, so that the mouse tumors would over-express VEGF. Then they compared results obtained with these mice to those obtained with control mice – whose tumors were from the unmodified cancer cell line (if I’m understanding this correctly). It looks like the chemo (carboplatin) treatment (without sunitinib pretreatment) was much worse on the VEGF-tumor mice than the mice whose tumors were from the unmodified cancer cell line. Still an indirect way of studying the role of VEGF/VEGF inhibition?